Transluminal drug delivery methods and devices

ABSTRACT

Transluminal drug delivery method and device embodiments can include a urethral suppository formulated to prevent or treat diseases of the urethra and surrounding organs, such as interstitial cystitis or urethritis, by enhancing the absorption of a therapeutic agent of the suppository into body tissues without adversely affecting the natural defense mechanisms of these tissues. Adverse effects on the glycosaminoglycan (GAG) barrier can be mitigated or eliminated by the presence of a suitable polysaccharide in the suppository.

CROSS-REFERENCES

This application is a continuation-in-part application of U.S. patentapplication Ser. No. 11/340,071 by Zupkas et al., entitled “TransluminalDrug Delivery Methods and Devices,” filed on Jan. 26, 2006, andincorporated herein in its entirety by this reference.

BACKGROUND OF THE INVENTION

Diseases of the urinary tract present a growing healthcare problemworldwide. One of the most common diseases of the urinary tract isinterstitial cystitis. Interstitial cystitis (IC) is a clinical syndromeof frequency, urgency, and/or pelvic pain in the absence of anydefinable pathology, such as urinary infection, carcinoma, or cystitisinduced by radiation or medication. A diagnosis of IC is often reachedas a diagnosis of exclusion, where patients have tried treatments forother diseases exhibiting similar symptoms and those treatments havefailed to alleviate the symptoms. The disease is best understood as acontinuum, with an early phase in which symptoms are intermittent, amiddle phase in which symptoms may be chronic and flare episodically,and sometimes a late phase in which bladder destruction occurs. In itsearly stages, IC is often mistaken for other urologic or gynecologicdisorders, and tends to go unrecognized until its advanced stages.Treatment options for IC are limited. There are few oral or intravesicalmedications that have shown efficacy in treating IC. Physicalintervention in the form of a cystectomy is used as a last resort in endstage disease. Although IC was traditionally diagnosed almostexclusively in women, the number of men diagnosed with IC has beenincreasing as well.

Although oral medications, such as pentosanpolysulfate (Elmiron®) andhyaluronic acid, are used to treat IC by replacing missing components ina defective glycosaminoglycan (GAG) barrier, a fundamentalcharacteristic of IC, the use of oral anesthetic agents to inhibiturinary tract sensory nerve activation is impractical. Oral drugdelivery affects the entire body, requiring high oral doses of drugs toachieve therapeutically significant levels in a target organ. When theorgan is in the urinary tract, such as the bladder or urethra, oraldrugs must pass through and be affected by other organs before reachingtheir target. This effect may change the activity or function of thedrug resulting in undesirable side effects or other co-morbidities. Analternative to oral delivery is topical or site-specific delivery of thedrug, where the drug is delivered directly to the diseased organ.Topical drug delivery generally provides similar efficacy at lower drugdoses than oral delivery, and may reduce or eliminate the effect of thedrug on any other organs than the target organ.

The use of urethral suppositories for topical drug delivery has beenknown. However, existing modalities do not allow for an efficientabsorption of some beneficial therapeutic agents. What have been neededare systems and methods for efficient delivery of therapeutic agents toat least a portion of the tissue of a patient's urinary tract, orsurrounding tissue thereof.

SUMMARY OF THE INVENTION

Some embodiments of a urethral suppository include a carrier basematerial, an anesthetic agent, and a buffering agent formed into a solidstructure configured for insertion into a patient's urethra. Suchembodiments can include a polysaccharide and can be prepared as asubstantially uniform composition. The carrier base material can have amelting point such that the suppository is substantially melted at bodytemperature. Alternatively, the carrier base material can be a watersoluble carrier base. Typically, the carrier base material is at leastone material selected from the group consisting of paraffin, theobromaoil, modified theobroma oil products, gelatins, glycerinated gelatins,polyethylene glycols (PEGs), glycerols, hydrogenated vegetable oils,cocoa butter, methyl butyl ketone (MBK), celluloses, polyvinyl alcohol,polyvinylpyrrolidone, polyacrylamide, polyphosphourethanes, polyoxylstearate, ethylene oxide polymers, and fatty acid bases. A preferredcarrier base material is methyl butyl ketone, which can further includeparaffin. If a polysaccharide is present, it is typically present in thesuppository in a sufficient quantity to prevent or ameliorate a urinarytract disorder. The urinary tract disorder can be, but is not limitedto, interstitial cystitis (IC) or urethritis. Typically, thepolysaccharide is at least one polysaccharide selected from the groupconsisting of hyaluronic acid, hyaluronan, chondroitin sulfate, pentosanpolysulfate, dermatan sulfates, heparin, heparan sulfates, keratansulfates, dextran sulfates, and carrageenan. A particularly preferredpolysaccharide is heparin.

Typically, the therapeutic agent is an anesthetic agent. Typically, theanesthetic agent is present in a quantity sufficient to prevent orameliorate a urinary tract disorder. Typically, the anesthetic agent isat least one anesthetic agent selected from the group consisting oflidocaine, benzocaine, bupivacaine, articaine, cocaine, etidocaine,flecainide, mepivacaine, pramoxine, prilocaine, procaine,chloroprocaine, oxyprocaine, proparacaine, ropivacaine, tetracaine,dyclonine, dibucaine, chloroxylenol, cinchocaine, dexivacaine,diamocaine, hexylcaine, levobupivacaine, propoxycaine, pyrrocaine,risocaine, rodocaine, and pharmaceutically acceptable derivatives andbioisosteres thereof, as well as combinations thereof. A preferredanesthetic agent is lidocaine.

Typically, the buffering agent is present in a quantity such that thebuffering agent buffers the suppository at a pH that ensures that asufficient portion of an anesthetic agent that is present in thesuppository is present in an uncharged state so that the anestheticagent can cross cell membranes of cells surrounding the urethra.Typically, the buffering agent maintains the pH of the suppository in arange of from about 7 to about 12; more typically, the buffering agentmaintains the pH of the suppository in a range of from about 7 to about9. Typically, the buffering agent is at least one buffer selected fromthe group consisting of sodium bicarbonate buffer, calcium bicarbonatebuffer, tris(hydroxymethyl)aminomethane (Tris or THAM), MOPS(3-(N-morpholino)propanesulfonic acid) buffer, HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) buffer, ACES(2-[(2-amino-2-oxoethyl)amino]ethanoesulfonic acid) buffer, ADA(N-(2-acetamido)2-iminodiacetic acid) buffer, AMPSO(3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer,BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, Bicine(N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris(bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS(3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO(3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES(2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO(3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid)buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N′-(3-propanesulfonic acid),buffer, HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid) buffer,MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolaminebuffer, imidazole buffer, glycine buffer, ethanolamine buffer, phosphatebuffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer,PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid) buffer, POPSO(piperazine-N,N′-bis(2-hydroxypropaneulfonic acid) buffer; TAPS(N-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer, TAPSO(3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid)buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid)buffer, tricin (N-tris(hydroxymethyl)methylglycine buffer),2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanolbuffer, as well as combinations thereof. Particularly preferredbuffering agents include sodium bicarbonate buffer andtris(hydroxymethyl)aminomethane buffer.

Typically, the suppository is from about 10 mg to about 1000 mg inweight; more typically, from about 400 mg to about 600 mg in weight.When the therapeutic agent is an anesthetic agent, the suppositorytypically comprises from about 1 mg to about 100 mg of anesthetic agent.More typically, the suppository comprises from about 30 mg to about 60mg of anesthetic agent. Typically, the suppository comprises from about0.5 mg to about 100 mg of buffering agent; more typically, thesuppository comprises from about 1 mg to about 20 mg of buffering agent.Typically, the suppository is in a configuration selected from the groupconsisting of a cylinder, a cone, and an ellipsoid. In one alternative,the suppository is an elongated structure with a transverse dimension offrom about 1 mm to about 10 mm; typically, the transverse dimension isfrom about 3 mm to about 6 mm. In another alternative, the suppositoryis an elongated structure with a length of from about 5 mm to about 50mm; typically, the length is from about 15 mm to about 35 mm. Typically,the suppository comprises a quantity of buffering agent that comprisesfrom about 1 percent to about 30 percent by weight of the overall weightof the suppository.

The suppository can further comprise a quantity of a suspending agentsufficient to prevent active ingredients within the suppository fromaggregating. The suspending agent can be silica.

The suppository can further comprise a therapeutically effectivequantity of an antibacterial agent or an antifungal agent to treatbacterial or fungal cystitis.

In another alternative, a urethral suppository according to the presentinvention can comprise a plurality of distinct layers, each layercomprising a carrier base material, a therapeutic agent, and a bufferingagent, wherein at least one of the identity of the carrier base materialin a layer, the identity of the therapeutic agent in a layer, theidentity of the buffering agent in a layer, the quantity of the carrierbase material in a layer, the quantity of the therapeutic agent in alayer, the quantity of the buffering agent in a layer, and the shape ofa layer varies between at least two of the layers of the suppository.The suppository can comprise two layers, three layers, or four layers;different numbers of layers are also possible. Typically, in thisalternative, the therapeutic agent in at least one layer of the urethralsuppository is an anesthetic agent. Alternatively, the therapeutic agentin at least two layers of the urethral suppository is an anestheticagent, and the anesthetic agents in two layers of the urethralsuppository are different anesthetic agents. In another alternative, theanesthetic agent in one layer of the urethral suppository is a firstanesthetic agent with a rapid onset and the anesthetic agent in anotherlayer of the urethral suppository is a second anesthetic agent with aslower onset than the onset of the anesthetic agent with a rapid onset,but with a longer half-life than the half-life of the anesthetic agentwith a rapid onset, the layer including the first anesthetic agent beinglocated closer to the surface of the urethral suppository than the layerincluding the second anesthetic agent. The first anesthetic agent can belidocaine, and the second anesthetic agent can be tetracaine.

In still another alternative, the therapeutic agent in one layer of theurethral suppository is an anesthetic agent, and the therapeutic agentin another layer of the urethral suppository is a therapeutic agentother than an anesthetic agent, the layer including the anesthetic agentbeing located closer to the surface of the urethral suppository than thelayer including the therapeutic agent other than an anesthetic agent.Typically, the anesthetic agent is lidocaine. The therapeutic agentother than an anesthetic agent can be selected from the group consistingof an anti-infection agent, an anti-incontinence agent, ananti-inflammatory agent, and an anti-cancer agent.

In still another alternative, the urethral suppository includes thereinat least two layers differing in the composition or quantity of thecarrier base material in the layers. The two layers can differ in theconcentration of an agent that regulates melting time, such as paraffin.

One or more of the layers can include a polysaccharide. If one or moreof the layers includes a polysaccharide, and at least one of theidentity of the polysaccharide in a layer and the quantity of thepolysaccharide in the layer can vary between at least two of the layersof the suppository. At least one of the layers can include a suspendingagent. At least one of the layers can include a therapeuticallyeffective quantity of an antibacterial agent or an antifungal agent.

In another possible alternative for multilayer urethral suppositoriesaccording to the present invention, at least one of the layers of thesuppository is shaped to focus the effect of the suppository in aspecific section of the suppository.

Some embodiments of a method for manufacturing a urethral suppositoryinclude combining an anesthetic agent and a buffering agent in a liquidcarrier base material until the anesthetic agent and the buffering agenthave dissolved or been suspended in the liquid carrier base material.The mixture of the liquid carrier base material, the anesthetic agent,and the buffering agent is then formed into a suppository that isconfigured to be deployed within a patient's urethra. Such embodimentscan also include combining a polysaccharide with the liquid carrier basematerial prior to the formation of the suppository. Typically, the stepof forming the mixture into a suppository results in a finishedsuppository having a weight of from about 10 mg to about 1000 mg.Typically, the quantity of buffering agent combined with the therapeuticagent in the liquid base material is sufficient to produce a pH of fromabout 7 to about 12 in the finished suppository.

A method for manufacturing a multilayered suppository according to thepresent invention comprises the steps of:

(1) combining a therapeutic agent and a buffering agent in a liquidcarrier base material until the therapeutic agent and the bufferingagent have dissolved or been suspended in the liquid carrier basematerial; and

(2) forming the liquid carrier base material, therapeutic agent, andbuffering agent mixture into one or more layers of a multi-layeredsuppository that is configured to be deployed within the urethra of apatient.

A method of treating at least a portion of the urinary tract of apatient using a multilayered suppository according to the presentinvention comprises the steps of:

(1) providing a multilayered urethral suppository according to thepresent invention as described above;

(2) deploying the multilayered urethral suppository within the patient'surethra; and

(3) allowing the multilayered suppository to disintegrate and releasethe therapeutic agent and the buffering agent from at least one of thelayers of the multilayered suppository to treat at least a portion ofthe urinary tract of the patient.

In this method, disintegration of the suppository can comprise meltingof the carrier base material of at least one layer of the suppository.Alternatively, in this method, disintegration of the suppository cancomprise dissolving the carrier base material of at least one layer ofthe suppository.

Some embodiments of a method of treating at least a portion of apatient's urinary tract comprise the steps of:

(1) providing a urethral suppository according to the present inventionas described above;

(2) deploying the urethral suppository within the patient's urethra; and

(3) allowing the suppository to at least partially disintegrate andrelease the therapeutic agent and the buffering agent to treat at leasta portion of the urinary tract of the patient.

Disintegration of the suppository can comprise melting of the carrierbase material of the suppository. Alternatively, disintegration of thesuppository can comprise dissolving the carrier base material of thesuppository.

When the therapeutic agent is an anesthetic, as described above,treating at least a portion of the urinary tract of the patient cancomprise treatment of interstitial cystitis. Alternatively, treating atleast a portion of the urinary tract of the patient can comprisetreatment of urethritis. In an other alternative, when the therapeuticagent is an anesthetic, the urethral suppository can be deployed withinthe urethra of the patient in order to desensitize the urethra prior toinsertion of instrumentation into the urethra. In yet anotheralternative, when the therapeutic agent is an anesthetic, treating atleast a portion of the urinary tract of the patient can comprise theprevention or treatment of pain associated with the urethra or bladder.The urethral suppository can further comprise a polysaccharide, asdescribed above, in which case the polysaccharide replaces or repairsthe glycosaminoglycan barrier lining the urinary tract of the patientafter insertion of the suppository into the urethra of the patient. Inanother alternative, the step of deploying the urethral suppositorywithin the patient's urethra can further comprise use of a water-basedlubricant.

Some embodiments of a depot for luminal drug delivery include a carrierbase material, a therapeutic agent, and a buffering agent formed into asolid structure configured for insertion into a body lumen of a patient.Such embodiments can also include a polysaccharide.

The depot can have a substantially uniform composition. The carrier basematerial can have a melting point such that the depot is substantiallymelted at body temperature. As described above, the therapeutic agent istypically an anesthetic agent such as lidocaine, although othertherapeutic agents can be incorporated into the depot. The carrier basematerial can be methyl butyl ketone. Alternatively, as described above,the carrier base material can be a water soluble carrier base.

These features of embodiments of the present invention will become moreapparent from the following detailed description when taken inconjunction with the accompanying exemplary drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an embodiment of a combination of acarrier base material, an anesthetic agent, a buffering agent, and apolysaccharide in liquid form being poured into a suppository moldcavity chamber.

FIG. 2 is a diagrammatic view of an embodiment of a combination of acarrier base material, an anesthetic agent, a buffering agent, and apolysaccharide in liquid form being poured into a suppository moldcavity embodiment showing the layers formed within the mold cavitychamber.

FIG. 3 is a perspective view of a urethral suppository embodiment.

FIG. 4 is a side view in partial section of a distal portion of adelivery catheter disposed within a urethra of a patient and a urethralsuppository being advanced distally within the delivery catheter.

FIG. 5 is a side view in partial section of the urethral suppositorydisposed within the urinary tract of the patient with the deliverycatheter withdrawn.

FIG. 6 is a graph showing the effect of lidocaine concentration on pHwith the incremental addition of sodium bicarbonate to a fluid volume of10 ml of water.

FIG. 7 is a graph showing the effect of lidocaine concentration on pHwith the incremental addition of sodium bicarbonate to a fluid volume of5 ml of water.

FIG. 8 is a graph showing the effect of fluid volume on pH with theaddition of sodium bicarbonate to a solution containing 30 mg oflidocaine.

FIG. 9 is a graph showing the effect of fluid volume on pH with theaddition of sodium bicarbonate to a solution containing 45 mg oflidocaine.

FIG. 10 is a graph showing the effect of fluid volume on pH with theaddition of sodium bicarbonate to a solution containing 60 mg oflidocaine.

FIG. 11 is a graph showing the results of lidocaine absorption as aresult of intravesical instillation and as a result of urethralsuppository administration with plasma lidocaine concentration plottedagainst time, with a 100 mg dose administered both intravesically and bysuppository.

FIG. 12 is a graph showing the data of FIG. 11 for urethral suppositoryadministration of lidocaine replotted on a different scale.

FIG. 13 is a graph showing the mean arterial blood pressure (MAP) afterurethral and suppository lidocaine administration.

FIG. 14 is a graph showing % of patients experiencing improvement intheir symptoms of pain (red, n=24) or urgency (yellow, n=19) as rated bya PORIS questionnaire 30 minutes after having a suppository with 10 mglidocaine, 5000 units heparin, with buffer and base.

FIG. 15 is a graph showing % of patients experiencing improvement intheir symptoms of pain (n=4) as rated by a PORIS questionnaire 30minutes after having a suppository with 10 mg lidocaine, 5000 unitsheparin with THAM (tris) buffer in place of bicarbonate and base.

FIG. 16 is a graph showing duration of pain relief of % of patients overtime when contacted 24 hours after the initial treatment (n=33). Themedian duration of relief was 4 hours.

FIG. 17 is a cross-section of a urethral suppository according to thepresent invention showing multiple layers.

FIG. 18 is a schematic representation of a two-layer suppositoryaccording to the present invention showing inner space for suppositorymaterial created by insert.

FIG. 19 is a schematic representation of a three-layer suppositoryaccording to the present invention showing inner space for suppositorymaterial created by insert.

FIG. 20 is a perspective view of a suppository being dipped into acontainer of melted suppository material to create an outer layer of amultilayer suppository using a dipping process.

FIG. 21 is a representation of a multilayer suppository according to thepresent invention that employs different geometries in the layers.

DETAILED DESCRIPTION OF THE INVENTION

There is currently no definitive diagnostic test for IC, although testssuch as the Potassium Sensitivity Test (PST) have been used to identifydefects that are fundamental characteristics of IC. The PotassiumSensitivity Test (PST) used a pain, urgency, and frequency questionnaireto identify patients who exhibit a positive reaction to the injection ofa concentrated potassium solution into their bladder. The basis for thetest is the identification of a fundamental characteristic of IC, whichis a breakdown of the glycosaminoglycan (GAG) barrier. Breakdown of theGAG barrier allows components in urine, such as potassium ions, to moveinto the interstitial spaces. As these components move into theinterstitial spaces, they activate sensory nerves that result in painand begin an inflammatory response. The inflammatory response begins acascade of events, including the activation of mast cell mediators,further activating sensory nerves resulting in more intense andprolonged pain. The inflammatory response is also considered to play akey role in the breakdown of the GAG layer. An objective in thetreatment of IC is to reduce the inflammatory response by inhibiting theactivation of sensory nerves. Inhibiting nerve activation reduces thepatient's pain and slows or stops the degradation of the GAG barrier.Inhibition of sensory nerves can be achieved using anesthetic drugs,such as lidocaine, procaine, and analogous local anesthetics, whichserve to inhibit ionic fluxes required for the initiation and conductionof nerve impulses.

In the urinary tract, the topical delivery of drugs requires overcomingthe natural GAG barrier that prevents materials from moving from theluminal space into the interstitium of the urinary tract. Thus, for atopically delivered drug to effectively treat IC, it must pass throughthe GAG barrier to reach the appropriate urinary tract tissues. At thesame time, as it passes through the GAG barrier, the drug must notdisable or damage the barrier or negatively affect its function inblocking harmful components in urine. The embodiments disclosed hereininclude methods for effectively delivering topical drugs to urethraltissue, surrounding tissue, or both, without adversely affecting the GAGbarrier of the urinary tract.

Although IC is considered a disease of the bladder, researches havedescribed a urethral component to the disease. This is not surprising asmany neural and systemic networks are shared by the bladder and urethra.Unlike the bladder, the urethra is a collapsed tube in its resting stageand open to allow urine to pass out of the bladder. Therefore, anyliquid or gel material placed in the urethra would be pushed out of theurethra into the bladder or out of the body. To treat the urethra, amedication can be incorporated into a structure that is retained in theurethra for a period of minutes to hours. Embodiments of a drug deliverysystem include a suppository base as a means to expose the urethra tomedication for periods of time from minutes to hours. The formulation ofthe delivery system including the type of base materials used as adelivery vehicle, the concentration of drug, and the ratio of drug tobuffering agent can be chosen so as to produce an efficient mechanismfor delivering the therapeutic agent. Size can be an important aspectfor the performance of a urethral suppository and for patient toleranceof the suppository, and thus is a consideration in any suppositoryformulation. The female urethra is approximately 3-4 cm in length. Mostpatients, both male and female, can tolerate an object placed in theirurethras up to about 19 Fr (6.3 mm) without major discomfort. Themaximum size of a urethral suppository that comfortably fits in thefemale urethra is about 2.5 cm in length and about 0.65 cm in diameteror transverse dimension. One difficulty with the performance ofpreviously available urethral suppositories has been formulating asuppository that fits comfortably in both the male or female urethra yetcontains enough drug to produce the desired therapeutic effect whilemaintaining the functional characteristics of a suppository.

Embodiments include a urethral suppository formulated to prevent ortreat symptoms of the urethra and surrounding organs due to urethralprocedures or diseases by enhancing the absorption of a drug included inthe suppository into body tissues without adversely affecting thenatural defense mechanisms of these tissues. This unique formulation isadapted to allow the active therapeutic agent to pass through the GAGbarrier that lines the urethra and the urinary tract. Adverse effects onthe GAG barrier that might otherwise be caused by the suppository can bemitigated or eliminated by the presence of a suitable polysaccharideincluded in the suppository formulation.

Embodiments of urethral suppositories include formulations including atherapeutic agent which is included in the suppository mixture. Onepreferred class of therapeutic agent is an anesthetic agent. Aparticularly preferred anesthetic agent is lidocaine, a neuronal sodiumchannel blocking agent. Lidocaine is a white solid substance that has anitrogen atom that can be protonated. The protonated form of lidocaineis a cation that has a positive charge, while the unprotonated form oflidocaine is neutral and thus uncharged. Typically, lidocaine isprovided in its protonated form, in which the positive charge isneutralized by a suitable counterion such as a chloride anion, forminglidocaine hydrochloride. When mixed with water, this form of lidocainecreates a solution that is acidic. For 2-5% lidocaine hydrochloridesolutions in sterile water, the pH range is from about 5 to about 6, orslightly acidic. It is known that the ionic, positively charge form oflidocaine is not readily absorbed into tissues of many body cavities andorgans. It is well known that ions generally have a difficult timepenetrating the hydrophobic lipid bilayers that form a major part ofcell membranes. This is due to the high free energy required.

However, buffering ionic lidocaine to a higher pH converts it to a lipidsoluble form of the drug because the nitrogen atom loses its proton andbecomes neutral. This neutral form of the drug is more readily absorbedinto tissues, because it more readily passes through the lipid bilayerof the cell membranes.

In its uncharged form, lidocaine is relatively nonpolar. The free,unprotonated lidocaine molecule is a weak base because of the presenceof the amide bond and the secondary amine group. However, the lidocainemolecule will be substantially protonated at a pH lower than the pKa oflidocaine. It will be substantially unprotonated at a pH higher than thepKa of lidocaine; if the pH of the solution is equal to the pKa oflidocaine, which is 7.8, the concentrations of the protonated andunprotonated forms of lidocaine will be equal. This relationship isexpressed mathematically by the Henderson-Hasselbalch equation:[Unprotonated]/[Protonated]=10^(pH−pKa).

As described above, lipid molecules are a primary component of cellmembranes and are known to be extremely hydrophobic. In the bladder andurethra, the lipid membranes of the urothelial cells are shielded fromdirect contact with urine by the presence of the GAG barrier. GAGmolecules readily attract water molecules creating a hydrated mucouslayer that is a primary component of the layer that lines the urethraand the bladder luminal wall. The water molecules in the hydrated mucouslayer have a slight negative charge that repels other negatively-chargedionic species. However, uncharged lidocaine molecules are nonpolar andas such are more lipophilic than hydrophilic; such lidocaine moleculescan still readily pass through the hydrated mucous layer. Accordingly,they easily and efficiently pass through the mucous layer and cellmembranes of the bladder and urethral tissue cells.

Although lidocaine is a preferred anesthetic, compositions and methodsaccording to the present invention are not limited to the use oflidocaine as an anesthetic component. Other anesthetics or combinationsthereof can be used, including, but not limited to, lidocaine,benzocaine, bupivacaine, articaine, cocaine, etidocaine, flecainide,mepivacaine, pramoxine, prilocaine, procaine, chloroprocaine,oxyprocaine, proparacaine, ropivacaine, tetracaine, dyclonine,dibucaine, chloroxylenol, cinchocaine, dexivacaine, diamocaine,hexylcaine, levobupivacaine, propoxycaine, pyrrocaine, risocaine,rodocaine, and pharmaceutically acceptable derivatives and bioisosteresthereof. Of these, beside lidocaine, preferred anesthetics includeprilocaine, benzocaine, mepivacaine, etidocaine, articaine, bupivacaine,procaine, and tetracaine.

Several carrier base materials and buffering agents can be used tocreate a buffered local anesthetic drug delivery system. Examples ofcarrier base materials can include, but are not limited to, paraffin,theobroma oil, modified theobroma oil products, gelatins, glycerinatedgelatins, polyethylene glycols (PEGs), glycerols, hydrogenated vegetableoils, cocoa butter, methyl butyl ketone (MBK), celluloses, polyvinylalcohol, polyvinylpyrrolidone, polyacrylamide, polyphosphourethanes,polyoxyl stearate, ethylene oxide polymers, fatty acid bases, and thelike. These materials can be used individually or in combination. Aparticularly preferred carrier base material is methyl butyl ketone. Inone alternative, the base material or base materials has a melting pointsuch that the suppository is substantially melted at body temperature.In another alternative, the base material or base materials have amelting point of from about 36° C. to about 38° C. In addition, acarrier base material that is water soluble can also be useful in somealternatives. The melting time of embodiments of the carrier basematerial or combination of carrier base materials can be adjusted by theaddition of paraffin to the liquid mixture to achieve a melting timefrom about 5 minutes to about 15 minutes.

Examples of buffering agents include, but are not limited to, sodiumbicarbonate buffer, calcium bicarbonate buffer,tris(hydroxymethyl)aminomethane (Tris or THAM), MOPS(3-(N-morpholino)propanesulfonic acid) buffer, HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) buffer, ACES(2-[(2-amino-2-oxoethyl)amino]ethanoesulfonic acid) buffer, ADA(N-(2-acetamido)2-iminodiacetic acid) buffer, AMPSO(3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer,BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, Bicine(N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris(bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS(3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO(3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES(2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO(3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid)buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N′-(3-propanesulfonic acid),buffer, HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid) buffer,MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolaminebuffer, imidazole buffer, glycine buffer, ethanolamine buffer, phosphatebuffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer,PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid) buffer, POPSO(piperazine-N,N′-bis(2-hydroxypropaneulfonic acid) buffer; TAPS(N-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer, TAPSO(3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid)buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid)buffer, tricine (N-tris(hydroxymethyl)methylglycine buffer),2-amino-2-methyl-1,3-propanediol buffer, 2-amino-2-methyl-1-propanolbuffer, or another buffer that can buffer the composition to beadministered at the appropriate pH value, as well as combinations ofthese buffers. The buffer to be selected, and the concentration of thebuffer to be used, can be chosen by one of ordinary skill in the art tobuffer the composition to be administered at a pH value that is close tothe isoelectric point of the local anesthetic. For lidocaine, this pHvalue is 7.9. For bupivacaine, it is 8.1. For etidocaine, it is 7.7.Typically, the pH achieved by the use of the buffer is between about 7.0and about 12.0. More typically, the pH achieved by the use of the bufferis between about 7.0 and about 9.5. Typically, when bicarbonate bufferis used, it is sodium bicarbonate buffer; however, other counterions canbe used as described above.

The carrier base material can further include additional components suchas preservatives. Suitable preservatives include, but are not limited tomethylparaben, ethylparaben, propylparaben, butylparaben, chlorphenesin,chlorobutanol, sorbic acid, thimerosal, and other preservatives commonlyused in the art for pharmaceutical compositions, includingsuppositories. Typically, the preservative is methylparaben orpropylparaben.

The carrier base material can further include an alkali as a pHadjusting agent to adjust the pH to an appropriate value. The alkali canbe, but is not limited to, sodium carbonate, sodium hydroxide, potassiumhydroxide, magnesium oxide, or another alkali. However, in manyapplications, particularly those in which the suppository is to beadministered as part of treatment of interstitial cystitis, it ispreferred to use alkalis in which the cation is other than potassium.This is because of the role that abnormal permeability of the urotheliumto potassium plays in the etiology of interstitial cystitis, soadministration of potassium salts is preferably avoided. The alkali isto be distinguished from the buffering agent.

One useful combination of carrier base material and buffering agent isMBK and sodium bicarbonate. The melting point of MBK can be adjusted toalter its disintegration rate via a melting process over a wide range oftime at body temperature. Adjustment of the melting point of MBK can becarried out by adding selected amounts of paraffin. MBK also has theability to dissolve lidocaine. Sodium bicarbonate can be useful as abuffering agent for some embodiments of urethral suppositories becauseit has the ability to buffer the pH value in the range of 8-9 incombination with lidocaine and the carrier base. Examples of suitableformulations are provided in the Examples below.

Silica can also be added as a suspending agent to prevent the activeingredients within the suppository from aggregating. The use of silicaor other suspending agent results in a suppository that has asubstantially uniform composition.

Urethral suppositories according to the present invention can be formedby mixing or combining components into a mixture and forming the mixtureinto a solid suppository. For example, such methods can includecombining a therapeutic agent in the form of an anesthetic agent and abuffering agent in a liquid carrier base material. As described ingreater detail below, a polysaccharide can also be combined with theliquid carrier base material before formation of the suppository. Thecombined components can be stirred, heated, or both until the anestheticagent and the buffering agent have been dissolved or suspended in theliquid carrier base material. For example, the carrier base material canbe warmed in a both having a temperature of from about 35° C. to about45° C. Once the carrier base material is warmed, a suitable anestheticagent, such as lidocaine, can be added. After the anesthetic agent hasdissolved or has been otherwise suspended in solution, the mixture cancontinue to be heated or have the temperature raised to a temperature offrom about 60° C. to about 80° C. Thereafter, the mixture can betitrated with a buffering agent, such as sodium bicarbonate, to a pH offrom about 7.5 to about 9 while gently stirring the mixture. In someembodiments, the mixture may lose its grainy appearance and become clearas all components are all dissolved in the carrier base material. Oncethe components have been suitably mixed, the liquid carrier basematerial, anesthetic agent, and buffering agent mixture can be formedinto a suppository or other type of solid depot that is configured to bedeployed within a patient's urethra or other body lumen.

FIG. 1 shows a perspective view of an embodiment of a combination of acarrier base material, an anesthetic agent, a buffering agent, and,optionally, a polysaccharide in a mixture 10 in liquid form being pouredfrom a container 11 into a suppository mold cavity 12. A mold body 14includes six individual mold cavities 12; each individual mold cavity 12has an elongated configuration with rounded or spherically shaped ends.Once one or more of the mold cavities 12 have been filed with thecombined mixture 10, the combined mixture 10 is allowed to harden and toform a solid structure. In some cases, the mold body 14 can berefrigerated overnight, after which the mixture 10 that has hardenedinto suppositories in the mold cavities 12 is removed from the mold; theresulting suppositories can be individually packaged for distribution orstorage. The suppositories can also be stored at lowered temperatures,such as from about 0° C. to about 10° C. prior to use.

FIG. 2 is a perspective view of mixture 10 being poured from container11 into a cylindrical suppository mold 16. The suppository mold 16 has abarrel shaped body portion 18 having a substantially round cross sectionwith a removable plug 20 disposed at the bottom of a mold cavity chamber22. After the mold cavity chamber 22 has been filled to a desired level,the combined mixture 10 containing the carrier base material, anestheticagent, buffering agent, and, optionally, polysaccharide is allowed toharden. Thereafter, the plug 20 can be removed and the newly formedsuppository pushed from the mold cavity chamber 22. The plug 20 can alsobe used to push the newly formed suppository from the mold cavitychamber 22.

FIG. 3 is a perspective view of a urethral suppository embodiment 24.The suppository 24 has an elongated cylindrical configuration withrounded or spherically shaped ends 26; however, other configurationssuch as conical or ellipsoidal can alternatively be used. As discussedabove, the size of the suppository 24 is a significant parameter in someapplications. In particular, for urethral suppositories 24, it can beuseful to have as large a suppository as possible while maintaining anacceptable level of patient discomfort. Some embodiments of a urethralsuppository 24 can have a length of about 5 mm to about 50 mm;typically, the length is from about 15 mm to about 35 mm. Suchembodiments can have a transverse dimension of from about 1 mm to about10 mm; typically, the transverse dimension is from about 3 mm to about 6mm. The overall weight of some embodiments of the suppository 24 can befrom about 10 mg to about 1000 mg; more typically, the overall weight isfrom about 50 mg to about 750 mg; preferably, the overall weight is fromabout 400 mg to about 600 mg. The overall weight can be chosen dependingon the appropriate size and shape of the suppository 24.

The carrier base material for the suppository can include a variety ofsuitable materials, as described above, including but not limited toparaffin, theobroma oil, modified theobroma oil products, gelatins,glycerinated gelatins, polyethylene glycols (PEGs), glycerols,hydrogenated vegetable oils, cocoa butter, methyl butyl ketone (MBK),celluloses, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide,polyphosphourethanes, polyoxyl stearate, ethylene oxide polymers, fattyacid bases, and the like. These materials can be used individually or incombination.

Suitable anesthetic agents for the suppository 24 can include lidocaine,benzocaine, bupivacaine, articaine, cocaine, etidocaine, flecainide,mepivacaine, pramoxine, prilocaine, procaine, chloroprocaine,oxyprocaine, proparacaine, ropivacaine, tetracaine, dyclonine,dibucaine, chloroxylenol, cinchocaine, dexivacaine, diamocaine,hexylcaine, levobupivacaine, propoxycaine, pyrrocaine, risocaine,rodocaine, and pharmaceutically acceptable derivatives and bioisosteresthereof, as well as combinations thereof. Preferred anesthetic agentsinclude lidocaine, prilocaine, benzocaine, mepivacaine, etidocaine,articaine, bupivacaine, procaine, and tetracaine. A particularlypreferred anesthetic agent is lidocaine. The anesthetic effect of all ofthese anesthetic agents will increase when mixed with suitable buffers.However, by mixing buffering agents at different concentrations withthese anesthetic agents, different anesthetic effects over varyingperiods of time can be achieved. It can be useful for some embodimentsto have a therapeutic agent that is configured to inhibit the conductionor initiation of nerve impulses. Typically, the quantity of anestheticagent incorporated in a suppository 24 according to the presentinvention is sufficient to prevent or ameliorate a urinary tractdisorder. Typically, the urinary tract disorder is interstitialcystitis. Alternatively, the urinary tract disorder is urethritis. Someembodiments of the urethral suppository 24 can include about 1 mg toabout 100 mg of anesthetic agent; typically, the urethral suppository 24includes from about 10 mg to about 75 mg of anesthetic agent; moretypically, the urethral suppository 24 includes about 30 mg to about 60mg of anesthetic agent. The quantity of anesthetic agent included in theurethral suppository 24 can be chosen according to the size and shape ofthe urethral suppository 24 and the disease or condition that theurethral suppository 24 is to treat.

Buffering agents that can be used for embodiments of the suppository 24can include buffering agents that are present in a quantity such thatthe buffering agent or agents buffers the suppository at a pH thatensures that a sufficient portion of an anesthetic agent that is presentin the suppository is present in an uncharged state so that theanesthetic agent can cross cell membranes of cells surrounding theurethra. Typically, the buffering agent can maintain a pH of theurethral suppository 24 in a range of from about 7 to about 12. Moretypically, the buffering agent can maintain a pH of the urethralsuppository 24 in a range of from about 7 to about 9. As describedabove, suitable buffering agents include, but are not limited to, sodiumbicarbonate buffer, calcium bicarbonate buffer,tris(hydroxymethyl)aminomethane (Tris or THAM), MOPS(3-(N-morpholino)propanesulfonic acid) buffer, HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) buffer, ACES(2-[(2-amino-2-oxoethyl)amino]ethanoesulfonic acid) buffer, ADA(N-(2-acetamido)2-iminodiacetic acid) buffer, AMPSO(3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer,BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, Bicine(N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris(bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS(3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO(3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES(2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO(3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid)buffer, HEPPS (N-(2-hydrox yethylpiperazine)-N′-(3-propanesulfonicacid), buffer, HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid) buffer,MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolaminebuffer, imidazole buffer, glycine buffer, ethanolamine buffer, phosphatebuffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer,PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid) buffer, POPSO(piperazine-N,N′-bis(2-hydroxypropaneulfonic acid) buffer; TAPS(N-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer, TAPSO(3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid)buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid)buffer, tricine (N-tris(hydroxymethyl)methylglycine buffer),2-amino-2-methyl-1,3-propanediol buffer, 2-amino-2-methyl-1-propanolbuffer, or another buffer that can buffer the composition to beadministered at the appropriate pH value, as well as combinationsthereof. Preferred buffering agents include sodium bicarbonate andtris(hydroxymethyl)aminomethane (Tris or THAM) buffer. A particularlypreferred buffering agent is sodium bicarbonate. Combinations ofdifferent buffering agents and anesthetic agents will have differentstability properties, affecting their efficacy when stored for longperiods of time. The choice of buffering agent can also be affected bythe ability of the buffering agent to maintain a uniform distribution ofthe anesthetic agent throughout the suppository 24. One of ordinaryskill in the art can make these determinations depending on parameterssuch as the stability of buffering agents and anesthetic agents, andphysical and chemical properties of buffering agents and anestheticagents including, but not limited to, molecular weight, molecularconformation, polarity, and relative hydrophobicity or hydrophilicity.Some embodiments of the urethral suppository 24 can include from about0.5 mg to about 100 mg of buffering agent. Typically, the urethralsuppository included from about 0.75 mg to about 50 mg of bufferingagent; more typically, the urethral suppository 24 includes from about 1mg to about 20 mg of buffering agent. The quantity of the bufferingagent in the urethral suppository 24 can be chosen according to the sizeand shape of the urethral suppository 24 and the disease or conditionthat the urethral suppository 24 is to treat. Some embodiments of theurethral suppository 24 can contain a quantity of buffering agent thatcomprises from about 1 percent to about 30 percent by weight of theoverall weight of the urethral suppository 24. Typically, the urethralsuppository 24 contains a quantity of buffering agent that comprisesfrom about 2.5 percent to about 20 percent of the overall weight of theurethral suppository 24. More typically, the urethral suppository 24contains a quantity of buffering agent that comprises from about 5percent to about 10 percent by weight of the overall weight of thesuppository 24. The urethral suppository 24 typically contains at leastone buffering agent selected from the buffers listed above.Alternatively, the urethral suppository 24 can contain a combination ofbuffering agents such that the combination of buffering agents iscompatible with the anesthetic agent or combination of anesthetic agentsand such that each buffering agent in the combination is compatible withthe other buffering agents in the combination and with other ingredientsin the suppository.

The composition of some embodiments, and particularly some of thebuffering agents and/or anesthetic agents, can include pharmaceuticallyacceptable salts. Pharmaceutically acceptable salts include, but are notlimited to, acetate, benzenesulfonate, besylate, benzoate, bicarbonate,bitartrate, bromide, calcium edetate, carnsylate, carbonate, citrate,edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate,napsylate, nitrate, pamoate (embonate), pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Otherpharmaceutically acceptable salts can be found in, for example,Remington, The Science and Practice of Pharmacy (20^(th) ed, Lippincott,Williams & Wilkins (2000)), which is incorporated herein in its entiretyby reference.

Embodiments of the urethral suppository 24 can further include apolysaccharide material, such as a mucopolysaccharide, configured toreplace or repair the GAG layer or barrier of at least a portion of apatient's urinary tract, such as the urethra. Typically, thepolysaccharide is an anionic polysaccharide. If present, thepolysaccharide is typically present in the urethral suppository 24 in asufficient quantity to prevent or ameliorate a urinary tract disorder.Typically, the urinary tract disorder is interstitial cystitis.Alternatively, the urinary tract disorder is urethritis.

The anionic polysaccharide is typically a glycosaminoglycan.Glycosaminoglycans are abundant naturally occurring polysaccharides thathave a net negative charge due to carboxylic acid or sulfate groups orboth. Although Applicants are not bound by this theory, thesepolysaccharides are believed to have protective effects on theepithelium and to counteract the abnormal permeability of the epitheliumto potassium that is characteristic of IC. Preferred anionicpolysaccharides include, but are not limited to, hyaluronic acid,hyaluronan, chondroitin sulfate, pentosan polysulfate, dermatansulfates, heparin, heparan sulfates, keratan sulfates, dextran sulfates,and carrageenan.

Heparin exists in a variety of forms characterized by different degreesof sulfation. Typically, heparin has a molecular weight of from about 2kDa to about 40 kDa. Heparin and heparan sulfate are both characterizedby repeating units of disaccharides containing a uronic acid (glucuronicacid or iduronic acid) and glucosamine, which is either N-sulfated orN-acetylated. The sugar residues can be further O-sulfated at the C-6and C-3 positions and the C-2 position of the uronic acid. There are atleast 32 potential unique disaccharide units in this class of compounds.Five examples of sugars occurring in heparin are: (1) α-L-iduronic acid2-sulfate; (2) 2-deoxy-2-sulfamino-α-D-glucose 6-sulfate; (3)β-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D-glucose, and (5)α-L-iduronic acid. Heparin is measured by its specific anticoagulationactivity in units. As used herein, the term “units” refers to specificactivity in International Units (IU) and/or United States Pharmacopoeia(USP) units. As used herein, the term “USP unit” refers to the quantityof heparin that prevents 1.0 ml of citrated sheep plasma from clottingfor 1 hour after the addition of 0.2 ml of 1% CaCl₂ at 20° C. whencompared to a USP reference standard (defined as units/ml). As usedherein, the term “International Unit” or “IU” refers to the quantity ofheparin that is active in assays as established by the FifthInternational standard for Unfractionated Heparin (WHO-5) (defined asInternational Units/ml) (Linhardt, R. J. & Gunay, N. S. (1999) SeminThromb Hemost 25, 5-16.). In some embodiments, heparin is a highermolecular weight species ranging from 8,000 to 40,000 daltons. As usedherein, “low-molecular-weight heparins” refers to a lower molecularweight (LMW) species ranging from 2,000 to 8,000 daltons. Also includedas glycosaminoglycans within the scope of the invention are pentosanpolysulfate sodium of molecular weight ranging from 4,000 to 6,000daltons, dalteparin, enoxaparin and the like. LMW heparins are made byenzymatic or chemical controlled hydrolysis of unfractionated heparinand have very similar chemical structure to unfractionated heparinexcept for some changes that may have been introduced due to theenzymatic or chemical treatment. While not intending to limit themechanism of action of the invention's compositions, it is theinventors' view that mechanism of action of these drugs is similar tothat of full-length heparin. LMW heparins are usually isolated from bulkheparin. Because of the negative charge of these polysaccharides due tothe occurrence of sulfate groups and/or carboxylic acid groups in them,they are administered in the form of salts, with an appropriate cationto neutralize the negative charges on the acid groups. Typically, thecation is sodium. However, other physiologically tolerable counterionsthat do not induce urinary tract dysfunctions such as magnesium andaluminum, as well as salts made from physiologically acceptable organicbases such as, but not limited to, trimethylamine, triethylamine,morpholine, pyridine, piperidine, picoline, dicyclohexylamine,N,N′-dibenzylethylenediamine, 2-hydroxyethylamine,bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine,dibenzylpiperidine, N-benzyl- β-phenethylamine, dehydroabietylamine,N,N′-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine,quinine, quinoline, and basic amino acids such as lysine and arginine,can be used. These cationic counterions can alternatively be used as thecounterions with anionic buffers such as bicarbonate, as well. Thesesalts may be prepared by methods known to those skilled in the art.However, it is generally undesirable to use potassium as a counteriondue to its role in the etiology of the conditions and syndromes beingtreated. Other glycosaminoglycans can be used in suppositories andmethods according to the invention, including low molecular weight (LMW)glycosaminoglycans, naturally derived glycosaminoglycans,biotechnologically prepared glycosaminoglycans, chemically modifiedglycosaminoglycans, and synthetic glycosaminoglycans.

Typically, when urethral suppositories 24 according to the presentinvention contain polysaccharide, the quantity of polysaccharide is fromabout 0.5 mg to about 100 mg of polysaccharide. More typically, thequantity of polysaccharide is from about 0.75 mg to about 50 mg ofpolysaccharide. Preferably, the quantity of polysaccharide is from about1 mg to about 20 mg of polysaccharide. The quantity of polysaccharide ina urethral suppository 24 according to the present invention can bechosen according to the size and shape of the urethral suppository 24and the disease or condition that the urethral suppository 24 is totreat, as well as the molecular weight of the polysaccharide and thespecific activity of the polysaccharide.

Silica can also be added as a suspending agent to prevent the activeingredients within the urethral suppository 24 from aggregating. Silicacan comprise from about 0.1 percent to about 5 percent by weight of aurethral suppository 24 according to the present invention. Typically,silica comprises from about 0.5 percent to about 2.5 percent by weightof a urethral suppository 24 according to the present invention. Othersuspending agents can alternatively be used and are well-known to thoseskilled in the art.

Once the urethral suppository 24 has been formed or otherwisemanufactured, it can be deployed within the body 28 of a patient 30 inorder to treat a variety of conditions, including IC, urethritis, painfrom a number of conditions, or employed for pre-procedure sensitizationor other uses. Although a human patient is depicted in FIG. 4 and theembodiments disclosed herein would be typically used for human patients,they can also be used in veterinary medicine to treat similar oridentical indications in animals. For example, they could be used totreat a socially or economically important animal such as a horse, acow, a sheep, a goat, a donkey, a mule, a dog, a cat, a pig, or anothersocially or economically important animal. FIG. 4 is a side view inpartial section of a distal portion 32 of a delivery catheter 34disposed within a urethra 36 of a patient. FIG. 4 illustrates thepatient's urinary tract including the bladder 38, bladder neck 40,urethra 42, and ureter 44. Also shown are some of the issues surroundingthe female patient's urinary tract including the labia minora 46,urethral os 48, vagina 50, and rectum 52. The urethral suppository 24 isshown being advanced distally within an inner lumen 54 of the deliverycatheter 34 towards the urethra 36 of the patient 30, as indicated byarrow 56. The delivery catheter 34 is an elongated tubular member havinga length of about 10 cm to about 100 cm, an outer transverse dimensionor diameter of about 19 Fr. and an inner lumen having an innertransverse dimension or diameter of up to about 10 mm. The deliverycatheter 34 can have any suitable construction, including that of anextruded polymer tube that can optionally be reinforced with braidedmaterial or the like. Materials such as polyethylene, polyurethane,nylon, or the like can be used. Once the suppository has been advancedto the distal portion 32 of the delivery catheter 34 and ejected from adistal end 58 of the delivery catheter 34, the delivery catheter 34 canbe withdrawn from the urethra 36 of the patient 30.

FIG. 5 shows the patient 30 of FIG. 4 with the suppository 24 disposedwithin the urethra, the delivery catheter 34 having been withdrawn. Oncethe suppository 24 has been deployed within the urethra 36 or other bodylumen, the carrier base material begins to disintegrate and therebydeliver the buffered anesthetic agent or other therapeutic agent totissues of the patient's urinary tract and surrounding tissue. Thedisintegration of the suppository can be carried out by dissolving ofthe carrier base material for some embodiments, particularly forembodiments having a water-soluble carrier base material. Thedisintegration of the suppository 24 can also occur due to melting ofthe carrier base material as a result of exposure to body temperaturewithin the urethra. In either modality, disintegration of the carrierbase material exposes the therapeutic agent or agents integrated intothe suppository structure 24.

The exact dosage delivered to patient 30 can depend on the subject to betreated, the age of the subject to be treated, the body weight of thesubject to be treated, the nature of the disease or condition for whichthe suppository is administered, such as, but not limited to,interstitial cystitis or urethritis, the severity and course of thedisease or condition of the subject to whom the suppository isadministered, the response of the subject, and pharmacokineticconsiderations such as liver and kidney function that affect themetabolism of any administered therapeutic agent. The optimalconcentration and dosage of the therapeutic agent, such as an anestheticagent, to be delivered can also depend on the specific therapeutic agentsuch as anesthetic used, the buffering agent used, the carrier basematerial used, and any optional polysaccharide used. These factors canbe determined by those of skill in the medical and pharmaceutical artsin view of the disclosure of the present application. Generally, atherapeutically effective dose is desired. A therapeutically effectivedose refers to that amount of the anesthetic agent or other therapeuticagent that results in a degree of amelioration of symptoms prior totreatment. As used herein, the term “treat” or equivalent terminology,including, but not limited to, terminology such as “ameliorate,” refersto any detectable improvement, whether subjective or objective, in theurinary tract disorder of the subject to whom the composition isadministered. For example, the term “ameliorate” can refer to animprovement as determined by the PORIS scale, PUF scale, or anycomponent of those scales; reduction of pain; reduction of urinaryfrequency; reduction of urinary urgency; reduction of requirement fornarcotic administration; reduction of incontinence; reduction ofabnormal permeability of the urothelium to potassium; or improvement inmore than one of these parameters. The term “ameliorate” does not stateor imply a cure for the underlying lower urinary tract condition.Alternatively, a dosage that prevents a symptom or condition of theurinary tract can be administered. The dosage forms containing effectiveamounts are within the bounds of routine experimentation, and therefore,are well within the scope of the embodiments disclosed herein. Ingeneral, however, a suitable dose of a buffered anesthetic for topicaldelivery can be in the range of from about 0.1 to about 10 mg/kg of bodyweight per day, typically in the range of from about 0.2 to about 5mg/kg of body weight per day, more typically in the range of from aboutpreferably in the range of from about 0.4 to about 2 mg/kg of bodyweight per day.

A urethral suppository 24 according to the present invention cancomprise additional ingredients. For example, the suppository 24 canfurther comprise a therapeutically effective quantity of anantibacterial agent or an antifungal agent to treat bacterial or fungalcystitis. Suitable antibacterial agents include, but are not limited to:(1) sulfonamides such as sulfanilamide, sulfadiazine, sulfamethoxazole,sulfisoxazole, sulfamethizole, sulfadoxine, and sulfacetamide; (2)penicillins such as methicillin, nafcillin, oxacillin, cloxacillin,dicloxacillin, ampicillin, amoxicillin, bacampicillin, carbenicillin,ticarcillin, mezlocillin, and piperacillin; (3) a combination oftrimethoprim plus sulfamethoxazole; (4) quinolones such as nalidixicacid, cinoxacin, norfloxacin, ciprofloxacin, orfloxacin, sparfloxacin,lomefloxacin, fleroxacin, pefloxacin, and amifloxacin; (5) methenamine;(6) nitrofurantoin; (7) cephalosporins such as cephalothin, cephazolin,cephalexin, cefadroxil, cefamandole, cefoxatin, cefaclor, cefuroxime,loracarbef, cefonicid, cefotetan; ceforanide, cefotaxime, cefpodoximeproxetil, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, andcefepime; (8) carbapenems such as imipenem, meropenem, and aztreonam;(9) aminoglycosides such as netilmycin and gentamicin; (10)tetracyclines such as tetracycline, oxytetracycline, demeclocycline,minocycline, doxycycline, and chlortetracycline; and (11) macrolidessuch as erythromycin, clarithromycin, and azithromycin. Antifungalagents include amphotericin B, itraconazole, ketoconazole, fluconazole,miconazole, and flucytosine. Other suitable antibacterial agents andantifungal agents are known in the art.

Additionally, still other ingredients can be included in a urethralsuppository 24 according to the present invention. Such ingredients caninclude, for example, a coloring agent, an antioxidant, a chelatingagent, and other ingredients typically used in pharmaceuticalformulations, including in suppositories. The use of preservatives isdescribed above.

Urethral suppositories according to the present invention can also beconstructed with multiple layers. A urethral suppository according tothe present invention can be constructed with two, three, or fourlayers, or more layers, with each layer having a different composition.Several altematives are possible for the multiple layers. For example,the layers can include the same anesthetic agent, buffering agent, and,if present, polysaccharide, but such that the concentrations of one ormore of these components vary from layer to layer. For example, thelayers can have the same concentration of buffering agent andpolysaccharide, but different concentrations of anesthetic agent. Asanother alternative, the layers can have different concentrations ofanesthetic agent and polysaccharide, but the same concentration ofbuffering agent. As still another alternative, the layers can havedifferent concentrations of buffering agent, anesthetic agent, andpolysaccharide. If silica or another suspending agent is present, itsconcentration can be varied between layers, or it can be omitted in oneor more of the layers. Similarly, if antibacterial or antifungal agentsare present, their concentration can be varied between layers or theycan be omitted in one or more layers. In another alternative, the layerscan include different anesthetic agents, buffering agents, orpolysaccharides if present. In this alternative, each of the layers caninclude a different anesthetic agent, buffering agent, orpolysaccharide. Alternatively, several of the layers could include thesame anesthetic agent, buffering agent, or polysaccharide, but one ormore additional layers could have a different anesthetic agent,buffering agent, or polysaccharide. The same arrangements can apply toadditional ingredients such as suspending agents, antibacterial agents,or antifungal agents; they can be varied between layers.

The construction of suppositories including multiple layers withdifferent compositions can be performed in a number of ways known tothose in the art. For example, but not by way of limitation, the layerscan be assembled sequentially from the inside out, so that a first layeris constructed and then a second layer is constructed on top of thefirst layer, so that a cross-section would show the first layer insidethe second layer and closer to the center of the suppository. Othermeans of construction of suppositories including multiple layers withdifferent compositions are known in the art.

In general, therefore, a urethral suppository according to thisembodiment comprises a plurality of distinct layers, each layercomprising a carrier base material, a therapeutic agent, and a bufferingagent, wherein at least one of the identity of the carrier base materialin a layer, the identity of the therapeutic agent in a layer, theidentity of the buffering agent in a layer, the quantity of the carrierbase material in a layer, the quantity of the therapeutic agent in alayer, the quantity of the buffering agent in a layer, and the shape ofa layer varies between at least two of the layers of the suppository.

In one alternative, the therapeutic agent in at least one layer of theurethral suppository is an anesthetic agent, as described above. Thetherapeutic agent in all layers of the urethral suppository can be ananesthetic agent. One or more of the layers can include apolysaccharide, as described above. Where more than one layer includes apolysaccharide, and at least one of the identity of the polysaccharidein a layer and the quantity of the polysaccharide in the layer can varybetween at least two of the layers of the suppository. One or more ofthe layers can include a suspending agent, as described above. One ormore of the layers can include a therapeutically effective quantity ofan antibacterial agent or an antifungal agent as described above.

In another alternative, the layers can include distinct classes of drugsto treat different disease states or provide different drug profiles, orpossess different formulations that would affect the physical propertiesof the suppository.

Multiple layers of suppository containing different classes of drugs maybe used to treat different diseases, which include, but are not limitedto infection, incontinence, inflammation or cancer. Suitableanti-infection agents, including but not limited to antibacterialagents, antifungal agents, antiprotozoal agents, and antiviral agents,are known in the art. Similarly, suitable anti-incontinence agents,including but not limited to anticholinergic agents such aspropantheline bromide and oxybutynin chloride, are known in the art.Anti-inflammatory agents, including, but not limited to, steroids andnon-steroidal anti-inflammatory drugs (NSAIDs), are known in the art.Anti-cancer agents, including, but not limited to, alkylating agents,antimetabolites, Vinca alkaloids, taxanes, epipodophyllotoxins,camptothecins, antibiotics, enzymes, biological response modifiers,platinum coordination complexes, anthracenediones, substituted ureas,methylhydrazine derivatives, adrenocortical suppressants, tyrosinekinase inhibitors, adrenocorticosteroids, progestins, estrogens,antiestrogens, androgens, antiandrogens, gonadotropin-releasing hormoneanalogues, and monoclonal antibodies, are known in the art. In oneexample, an anti-cancer agent may be incorporated in the inner layer ofa suppository, while the outer layer of suppository contained ananesthetic agent such as lidocaine as described above. In this manner,cancer agents that caused discomfort or pain to the patient could beused because of the anesthetic effect of the anesthetic agent in theouter layer of the suppository. In another example, the outer layer caninclude a first anesthetic agent with a rapid onset, but shorthalf-life, such as lidocaine, while the inner layer includes a secondanesthetic agent with a slower onset, but much longer half-life, such astetracaine. In this manner, the anesthetic effect to the urethra couldbe made to occur quickly and last many hours longer than with asuppository containing a single anesthetic agent.

Multiple layers of suppository may also be fabricated to incorporatedifferent formulations to affect the physical properties of the layer,such as melting or dissolution time. Typically, these differentformulations alter the composition or quantity of the carrier basematerial. In one example, the outer layer of a multi-layer suppositorycan comprise a formulation with a reduced concentration of the agentused to regulate melting time, such as paraffin, while the inner layercontained a higher concentration of the same agent to increase meltingtime. The outer layer would melt quickly, exposing the urethra to aloading dose of anesthetic agent, while the inner layer would meltslower, providing the urethra a maintenance dose of the same anestheticagent. In this manner, the anesthetic and therapeutic effect of thesuppository would provide an immediate effect that was extended beyondwhat was achievable by a single layer suppository.

Although the examples presented above describe two layer suppositories,it should be recognized that suppositories including three or morelayers are possible and are limited only by the desired final size andthe methods used to fabricate the suppository; these multiple layersuppositories can include various arrangements of the layers.Fabrication methods can include, but are not limited to, insert moldingor dipping processes. The insert molding process would use one or moreinserts that would be placed inside a mold cavity. The outer layer ofthe suppository would be formed first by pouring the melted suppositorymaterial into a mold cavity with an insert that would be removed afterthe material had cooled and hardened leaving a hollow space within thesuppository. A second material can then be poured into the hollow spaceto form the inner layer of the suppository. Alternatively, a secondsmaller insert could be inserted to form a third hollow space within thesecond material for a third material. This same process could befollowed as often as practical to create a multilayered suppository.

Insert molding produces suppositories with layers that contain veryaccurately measured amounts of drugs and ingredients. However, theinsert molding process involves many steps, thus making it expensive andcomplex. A less expensive, but less accurate method for fabricatingmultilayered suppositories is using a dipping process. The first step isto form the innermost layer is using conventional suppositoryfabrication methods. The formed suppository is then dipped in a secondmaterial. Changing parameters of the dipping process can regulate thethickness of the second layer of material. These parameters include, butare not limited to, the viscosity of the second material, the speed ofwithdrawal of the suppository from the second material and thetemperature of each component in the system. This process can berepeated to create multilayered suppositories.

Finally, it should be recognized that the multilayered suppository canbe fabricated such that the geometry of the individual layers aredifferent from the geometry of the total suppository or from oneanother. A layer of suppository material may be thickened or thinned orshaped to focus its effect in a specific section of the suppository. Theadvantages of such a multilayered suppository structure are to providemore or less drug to specific areas of the urethra, such as theprostate, a urethral sphincter, or the bladder neck. The complexity ofthe different geometries is limited in some part by the fabricationprocess, with insert molding techniques providing more flexibility thandipping processes in creating more complicated and precise geometries.

These multiple layers are shown in FIG. 17. The urethral suppository 124is shown in cross section with three layers: a first layer 126 closestto the center of the suppository 124; a second intermediate layer 128;and a third layer 130 closest to the outside of the suppository 124. Theurethral suppository 124 can be constructed with more or fewer layers.

FIG. 18 is a schematic representation of a two-layer suppositoryaccording to the present invention showing inner space for suppositorymaterial created by an insert. In FIG. 18, the suppository mold 140 forthe outer layer of the suppository forms the space for the outer layer142 of the suppository material, leaving an inner space 144 for thesecondary (interior) layer of the suppository material. The inner space144 for the secondary (interior) layer of the suppository material iscreated by an insert 146.

FIG. 19 is a schematic representation of a three-layer suppositoryaccording to the present invention showing inner space for suppositorymaterial created by an insert. In FIG. 19, the suppository mold 160 forthe outer layer of the suppository forms the space for the outer layer162 of the suppository material. The inner layer 164 of the secondarysuppository material is located inside the outer layer 162; the innerlayer 164 is shaped to leave an inner space 166 for the tertiarysuppository material. The inner space 166 for the tertiary suppositorymaterial is created by an insert 168.

FIG. 20 is a perspective view of a suppository being dipped into acontainer of melted suppository material to create an outer layer of amultilayer suppository using a dipping process. The inner layer of thesuppository 170 is dipped into a container 172 of melted suppositorymaterial to form the outer layer (not shown).

FIG. 21 is a representation of a multilayer suppository employingdifferent geometries (shapes) in the layers. In FIG. 21, the suppository180 includes an outer primary layer 182 and an inner secondary layer184. The outer primary layer 182 and the inner secondary later 184 havedifferent geometries for optimal delivery of the therapeutic agentincluded in the suppository 180.

The present invention is not limited to urethral suppositories. Theprinciples underlying the invention can also be used to construct adepot for luminal drug delivery. In general, a depot for luminal drugdelivery according to the present invention comprises: (1) a carrierbase material; (2) a therapeutic agent; and (3) a buffering agent,wherein the depot is formed into a solid structure configured forinsertion into a body lumen of a patient.

The depot can have a substantially uniform composition. The depot canfurther comprise a polysaccharide such as a glycosaminoglycan asdescribed above. The carrier base material can have a melting point suchthat the depot is substantially melted at body temperature. Thetherapeutic agent can be an anesthetic agent such as lidocaine, asdescribed above. In one alternative, the carrier base material comprisesa water soluble carrier base, as described above. In anotheralternative, the carrier base material comprises methyl butyl ketone, asdescribed above; the carrier base material can further comprise paraffinto adjust the desired melting temperature.

The shape and dimensions of the depot can be determined by one ofordinary skill in the art with reference to the shape and dimensions ofthe lumen of the body into which the depot is intended to be inserted.

Another aspect of the present invention is a method for manufacturing aurethral suppository. In general, the method comprises the steps of:

(1) combining a therapeutic agent and a buffering agent in a liquidcarrier base material until the therapeutic agent and the bufferingagent have dissolved or been suspended in the liquid carrier basematerial; and

(2) forming the liquid carrier base material, therapeutic agent, andbuffering agent mixture into a suppository that is configured to bedeployed within the urethra of a patient.

The method can further comprise combining a polysaccharide with theliquid carrier base material, as described above, to form a suppositoryincluding the polysaccharide. The polysaccharide can be selected fromthe group consisting of hyaluronic acid, hyaluronan, chondroitinsulfate, pentosan polysulfate, dermatan sulfates, heparin, heparansulfates, keratan sulfates, dextran sulfates, and carrageenan asdescribed above.

Typically, the step of forming the mixture into a suppository results ina finished suppository having a weight of from about 10 mg to about 1000mg.

Typically, the therapeutic agent is an anesthetic agent as describedabove, such as lidocaine.

Typically, the quantity of buffering agent combined with the therapeuticagent in the liquid base material is sufficient to produce a pH of fromabout 7 to about 12 in the finished suppository.

Methods for manufacturing a urethral suppository that are within thescope of the present invention also include methods for manufacturing amultilayered suppository as described above. In general, such methodscomprise the steps of:

(1) combining a therapeutic agent and a buffering agent in a liquidcarrier base material until the therapeutic agent and the bufferingagent have dissolved or been suspended in the liquid carrier basematerial; and

(2) forming the liquid carrier base material, therapeutic agent, andbuffering agent mixture into one or more layers of a multilayeredsuppository that is configured to be deployed within the urethra of apatient.

Another aspect of the present invention is a method of treating at leasta portion of the urinary tract of a patient comprising the steps of:

(1) providing a urethral suppository according to the present inventionas described above;

(2) deploying the urethral suppository within the patient's urethra; and

(3) allowing the suppository to at least partially disintegrate andrelease the therapeutic agent and the buffering agent to treat at leasta portion of the urinary tract of the patient.

In one alternative, disintegration of the suppository comprises meltingof the carrier base material of the suppository. In another alternative,disintegration of the suppository comprises dissolving of the carrierbase material of the suppository.

Typically, the therapeutic agent is an anesthetic agent, such aslidocaine, as described above. When the therapeutic agent is ananesthetic agent, in one alternative, treating at least a portion of theurinary tract of the patient comprises treatment of interstitialcystitis. Alternatively, treating at least a portion of the urinarytract of the patient comprises treatment of urethritis. When thetherapeutic agent is an anesthetic agent, in another alternative, theurethral suppository is deployed within the urethra of the patient inorder to desensitize the urethra prior to insertion of instrumentationinto the urethra. When the therapeutic agent is an anesthetic agent, instill another alternative, treating at least a portion of the urinarytract of the patient comprises treatment of pain associated with theurethra or bladder.

In this method, the urethral suppository can further comprise apolysaccharide; the polysaccharide replaces or repairs theglycosaminoglycan barrier lining the urinary tract of the patient afterinsertion of the suppository into the urethra of the patient.

In methods according to the present invention, the exact formulation anddosage used in suppositories according to the present invention can bechosen by the individual physician in view of the patient's condition.(See e.g. Fingl et al., in The Pharmacological Basis of Therapeutics,1975, Ch. 1 p. 1). It should be noted that the attending physician wouldknow how to and when to terminate, interrupt, or adjust administrationdue to toxicity, or to organ dysfunctions. Conversely, the attendingphysician would also know to adjust treatment to higher levels if theclinical response were not adequate (precluding toxicity). The magnitudeof an administered dose in the management of the disorder of interestwill vary with the severity of the condition to be treated, the generalcondition of the urinary tract, including the bladder and urethra, andthe existence of other conditions affecting the urinary tract, such asinfections, inflammation, or allergic reactions. The severity of thecondition may, for example, be evaluated, in part, by standardprognostic evaluation methods. Further, the dose, and perhaps the dosefrequency, will also vary according to the age, body weight, andresponse of the individual patient. A program comparable to thatdiscussed above may be used in veterinary medicine.

Particularly when methods according to the present invention are used totreat interstitial cystitis, the method can further comprise theadministration of an additional oral agent that acts to reduce abnormalpermeability of bladder epithelium, so that the frequency of suppositoryuse can be reduced according to the response of the patient. A suitableoral agent is pentosan polysulfate. Typically, when pentosan polysulfateis administered, the quantity used is from about 100 mg/day to about 600mg/day; more typically, the quantity used is from about 100 mg/day toabout 300 mg/day.

Particularly when methods according to the present invention are used totreat interstitial cystitis, the method can further comprise theadministration of another agent such as a steroidal anti-inflammatoryagent. Steroidal anti-inflammatory agents include, but are not limitedto, alclometasone, amcinonide, beclomethasone, betamethasone,budesonide, clobetasol, clocortolone, hydrocortisone, cortisone,desonide, desoximetasone, dexamethasone, diflorasone, fludrocortisone,flunisolide, fluocinolone, fluocinonide, fluorometholone,flurandrenolide, halcinonide, medrysone, methylprednisolone, mometasone,prednisolone, prednisone, and triamcinolone, and their salt forms.

Again, particularly when methods according to the present invention areused to treat interstitial cystitis, the method can further comprise theadministration of other pain agents in addition to the anesthetic agentadministered via suppository, such as calcium T-type channel blockerswhich include, but are not limited to neurontin (gabapentin) andpregabalin; non-steroidal anti-inflammatory drugs (NSAIDs) whichinclude, but are not limited to ketoprofen, ibuprofen, and ketorolac; orNMDA antagonists which include, but are not limited to ketamine.

The step of deploying the urethral suppository within the patient'surethra can further comprise use of a water-based lubricant. A certainfraction of patients who receive a suppository complain of burning intheir urethra the first 2-4 minutes before the anesthetic agent takeseffect. The anesthetic effect lasts 2-4 hours. The burning returns inthese patients during their first void after the anesthetic wears off.Typically, these patients do not present, via PUF scores or patienthistory, as the most severe cases of IC. A solution to this problem isto coat the suppositories in a water-based lubricant prior to insertion.Three patients in the clinic, who had previously complained of burning afew hours after inserting a suppository, experienced no discomfort oninsertion and no burning associated with voiding many hours afterinsertion (on the order of 2-8 hours).

There are two theories as to why this solution works. The first involvesthe hydrophilic nature of heparin acting almost as a desiccant in thesuppository. By attracting water out of already fragile GAG layer due todisease, the heparin is exposing the interstitium to an even greaterthan usual potassium leak. The burning lessens and disappears after thefirst void as the heparin and the GAG layer become fully hydrated. Thegel acts to hydrate the suppository and urethra, maintaining the GAGlayer and preventing the potassium leak. The second is more mechanicalin nature and involves irritation to the urethra as a result of therubbing of the suppository on the urethra during insertion. Thesepatients who experience post-suppository burning after voiding may haveultrasensitive urethras that react to the slightest physical contact.This contact may cause an immediate inflammatory response or a physicalabrasion of the GAG. The gel in this situation acts as a lubricant thatreduces the frictional contact between the urethra and suppository.Suitable lubricants include, but are not limited to, lubricantscomprising water, glycerol, polyethylene glycol, and nontoxicpreservatives such as parabens. This also applies to methods oftreatment using multilayered suppositories according to the presentinvention as described below.

Methods of treatment according to the present invention also encompassmethods of treatment using a multilayered suppository as describedabove. In general, such methods comprise the steps of:

(1) providing a multilayered urethral suppository according to thepresent invention as described above;

(2) deploying the multilayered urethral suppository within the patient'surethra; and

(3) allowing the multilayered suppository to disintegrate and releasethe therapeutic agent and the buffering agent from at least one of thelayers of the multilayered suppository to treat at least a portion ofthe urinary tract of the patient.

The invention is illustrated by the following Examples. These Examplesare included for illustrative purposes only, and are not intended tolimit the invention.

EXAMPLE 1

Suppository Fabrication

Animal tests, using a New Zealand White rabbit model, were conducted todetermine the safety profile of buffered lidocaine absorption bymeasuring plasma levels of lidocaine in the systemic circulation usingdifferent carrier bases. Levels of lidocaine that would be toxic ifinjected intravenously were fabricated in a suppository carrier base.Different carrier bases were warmed in a 40° C. base and lidocaine wasadded in increments of 10% of the final weight of the mixture until itreached a ratio of 3:7 lidocaine to carrier base. The pH of the mixturewas measured after all lidocaine had dissolved using a temperaturecompensating pH meter. A 30% lidocaine mixture was found to be thehighest concentration lidocaine mixture achievable with the carrier basematerials that were tried. The mixture was raised to 70° C. in a waterbath and titrated with sodium bicarbonate to a pH of 8.5 while themixture was gently stirred. Heating and stirring were stopped when themixture lost its grainy appearance and became clear as all componentsdissolved in the carrier base. The mixture was drawn into tuberculinsyringes, refrigerated overnight to form suppositories, and extruded thenext day. The extruded suppositories were cut into thirds formingelongated sections having a length of about 2 cm and containingapproximately 100 mg of lidocaine.

Urethral Insertion

Female New Zealand White rabbit subjects having a weight range of fromabout 3.5 kg to about 3.8 kg were anesthetized using intramuscularinjections of ketamine and xylazine followed by half doses every hour asneeded. The common carotid artery was exposed and cannulated to provideblood pressure measurements using a Life-Tech BP2110 pressure transducerand to draw blood. Another incision was made in the abdomen to exposethe bladder. Through a small incision in the dome of the bladder, a 7 Frpediatric feeding tube was placed in the bladder. All urine was drainedfrom the bladder. The tube was fed out the bladder through the urethraand out the urethral opening. The suppositories were attached to lengthsof 3-0 silk sutures that were fed through the tube and out the bladderincision. The tube was removed and the suture pulled through theincision, drawing the suppository into the urethra. The bladder incisionwas closed. Blood samples were drawn at 0, 15, 30, 60, and 90 minutes.After 90 minutes, the animals were sacrificed and their urethras removedand placed in a 10% formaldehyde solution for histological study.

Results

Free lidocaine was measured in plasma samples using the AbbottLaboratories TDx sheep albumin immunofluorescence assay. This assay isaccurate for lidocaine levels from about 1-7 μg per ml of plasma. Thisassay was chosen for the reason that it is the standard means by whichlidocaine concentration is measured for therapeutic purposes or in casesof suspected toxicity. In all carrier base mixtures, the maximumconcentration of lidocaine in the blood was less than the resolution ofthe assay at 60 and 90 minutes after introduction. The maximumconcentrations were observed between 15 and 30 minutes and did notexceed 1.1 μg of lidocaine per ml of plasma in all subjects. No subjecthad a measurable amount of lidocaine in its blood after 30 minutes. Nosignificant hemodynamic changes were observed. The level of lidocaineadministered to all subjects was a full order of magnitude greater thanthe currently prescribed clinical dose of analgesic lidocaine. Even atthis elevated dose, the blood levels of lidocaine did not reach thethreshold for a therapeutic effect (2-5 μg per ml) or toxic level(greater than 8 μg per ml). Histological examination of post-insertionurethras using hematoxylin/eosin (H & E) stain revealed an inflammatoryresponse in epithelial cells lining the luminal urethra in subjectreceiving suppositories using a polyethylene glycol (PEG) carrier base.All other suppository carrier materials revealed normal cellularstructure in the urethral cells.

No subject voided after insertion of the lidocaine urethral drugdelivery mixture or after instillation of an alkalinized lidocainesolution. These results suggest that a buffered urethral delivery oflidocaine reduces patient exposure to toxic lidocaine levels, asevidenced by the low peak values of plasma lidocaine. In addition, thecessation of voiding after the administration of lidocaine implies thatthe drug is acting as a local anesthetic in the bladder and urethra. Insuch a case the amount of lidocaine transported into the tissue wassufficiently great to block nerve conduction and provide analgesiawithout exposing the subject to perilous plasma lidocaineconcentrations.

EXAMPLE 2

Human clinical studies were conducted to determine the efficacy of abuffered lidocaine suppository having a mucopolysaccharide component torepair any defect or injury to a luminal surface of a patient's urethra.A conical suppository with a weight of approximately 500 mg was used inthe study. Suppositories were fabricated to contain approximately 10%lidocaine buffered to a pH of about 7.8. Methyl butyl ketone (MBK) waschosen as the suppository carrier base material, because the meltingtime of the base material could be adjusted by addition of paraffin to amelting time within a range of 5-15 minutes. Suppositories werefabricated with PEG but without any active ingredient to determine ifthe inflammatory response observed in the animals resulted in anyadverse effects in humans. Suppositories containing PEG carrier basematerials were placed in two human subjects with both subjectscomplaining of urethral burning and urinary frequency. As a result, PEGwas not used clinically in any further suppository formulation in theseExamples. The suppository formulation used in the clinical study was asfollows:

Ingredient Quantity Therapeutic Agents Lidocaine 45 mg Heparin 5000units Sodium Bicarbonate 10 mg Silica 10 mg Base Materials Methyl ButylKetone 383 mg Paraffin 67 mg

These carrier base materials were melted in a water bath at 60° C. andthoroughly mixed. The lidocaine, heparin, sodium bicarbonate, and silicawere added to the carrier base materials while the mixture was gentlystirred. After all suppository components were dissolved, the mixturewas drawn into a syringe and injected into the cavities of thesuppository mold. The mold was refrigerated overnight, after which thesuppositories were removed from the mold and individually packaged. Allsuppositories were stored at 5° C. prior to use.

A total of 25 patients with a clinical diagnosis of IC with a urethralcomponent determined by a score of greater than 15 out of 20 on a pain,urgency, and frequency (PUF) questionnaire received the bufferedlidocaine suppositories. Patients were asked to grade their level ofpain and discomfort pre- and post-insertion of the suppository. Beforeinsertion of the suppository, patients graded their pain and discomfortat 8 on a 10 point analog pain scale with 10 being the highest degree ofpain and discomfort and 0 being none. Patients graded their pain anddiscomfort 30 minutes after insertion of the suppository at 3 on the 10point analog pain scale.

EXAMPLE 3

The study of Example 3 investigates the amount of sodium bicarbonatenecessary to buffer a lidocaine solution to a pH of 7.6-7.8. Sodiumbicarbonate in 3 mg increments was added to three concentrations oflidocaine in two volumes of water. The three concentrations of lidocainewere 30, 45, and 60 mg. The rationale for this choice of lidocaineconcentrations was they represent a 5-12% range of lidocaineconcentrations, by weight, in the 500 mg suppository expected to be usedin future clinical studies. This range of lidocaine concentrations inthe suppository covers what will most likely be the lidocaineconcentration used in the final clinical version of a buffered lidocainesuppository.

To measure pH, the lidocaine and sodium bicarbonate must be dissolved insolution. However, lidocaine and sodium bicarbonate are not dissolved inthe suppository. Rather, they are in suspension in the carrier base anddissolve only after they are released from the carrier base and exposedto an aqueous environment surrounding tissue. Because it is difficult orimpossible to know how quickly the lidocaine/sodium bicarbonate isreleased and how much water is surrounding the suppository, we mustunderstand how the pH of the lidocaine/sodium bicarbonate combination isaffected by the amount of water in which the combination is dissolved.Two volumes of water, 5 and 10 ml, near the lower limits of fluidvolumes required for measurement by the pH meter, were used to determinethe effect of fluid volume on pH of the lidocaine/sodium bicarbonatemixture.

The study was conducted using an Omega PBH-45 pH meter. The lidocainewas dissolved in deionized water in a glass beaker. Sodium bicarbonatewas added in increments of 3 mg, starting from 0 mg up to 12 mg. The pHwas measured after each increment of sodium bicarbonate was thoroughlydissolved. Each study was repeated 4 times. The results of all studiesare shown in FIGS. 6-10. In FIGS. 6 and 7, the effect of lidocaineconcentration on pH was examined as sodium bicarbonate was incrementallyadded to two fluid volumes (10 ml for FIG. 6; 5 ml for FIG. 7). In FIGS.8-10, the effect of fluid volume on pH was examined as sodiumbicarbonate is added to three lidocaine solutions (30 ml for FIG. 8, 45ml for FIG. 9, and 60 ml for FIG. 10).

The results of this study showed that a pH of 7.6-7.8 for a 5% or 10%buffered lidocaine suppository, approximately 550 mg total weight, isachieved with the use of approximately 5 mg and 10 mg, respectively, ofsodium bicarbonate. Fluid volume does not appear to have a major effecton the relationship between lidocaine and sodium bicarbonate indetermining the pH of the solution. Coupling this knowledge with a lackof understanding of the fluid volume into which the lidocaine/sodiumbicarbonate mixture would be released from the suppository, our 5% and10% lidocaine suppository formulations used the 5 mg and 10 mg sodiumbicarbonate formulations, respectively.

EXAMPLE 4

The purpose of the study reported in Example 4 was to investigate thesafety of placing a lidocaine suppository in the urethra. Lidocainesuppositories containing an ×5 clinical lidocaine dose were used in arabbit model. Clinical safety was determined by measuring plasmalidocaine levels as a result of absorption of lidocaine in the urethra,through tissue, and into the systemic circulation. Plasma lidocainelevels were measured using a TDx/TDxFLx free lidocaine assay. The plasmalevel of lidocaine considered to be clinically toxic is 6-8 μg/ml ofplasma. For comparative purposes, a parallel study was conducted toinvestigate the safety of a similar dose of lidocaine injected directlyinto the bladder.

The lidocaine suppositories were fabricated by dissolving lidocainebuffered with sodium bicarbonate to a pH of 8 in a glycerinated gelatinbase at 70° C. The suppositories were drawn into a tuberculin syringeand formed into cylindrical shapes with a final concentration ofapproximately 100 mg of lidocaine/suppository. A 3-0 silk suture wasdrawn through the axis of the suppository to aid in the positioning ofthe suppository in the rabbit urethra.

Female New Zealand White rabbits, 3.5-4 Kg, were anesthetized using amixture of ketamine and xylazine. A cannula was placed in the rightcarotid artery to obtain blood samples and monitor arterial pressureduring the entire procedure. A 6 Fr Foley catheter was placed throughthe urethra via a suprapubic bladder route. The suture was fed throughthe catheter and out the suprapubic access site. The catheter was thenremoved and the suture was drawn out of the bladder as to position thesuppository in the middle urethra. For intravesical instillation, a 6 Frcatheter was placed transurethrally in the bladder and all urinedrained. A 5 ml solution of 100 mg of lidocaine was then instilled inthe bladder through the catheter. Plasma samples were drawn through thecarotid cannula at 0, 15, 30, 60, 90, and 120 minutes.

The results of the lidocaine absorption are shown in FIG. 11. Plasmalevels of urethral lidocaine were less than 10% of intravesicallidocaine for all sample times. Intravesical lidocaine absorption showeda rapid rise to a peak level of over 35 μg/ml, then a fast decline to 5μg/ml in 60 minutes. In contrast, urethral absorption of lidocaine neverrose above 1 μg/ml and remained relatively steady for the entiremeasurement period; see FIG. 12. Urethral absorption did not causesignificant hemodynamic changes as reflected in the mean arterialpressure (MAP), shown in FIG. 13.

Lidocaine absorption is much less through the urethra than the bladderat the same dose, 100 mg for the current study. The maximum recommendedadult dose of lidocaine hydrochloride is 4.5 mg/Kg (PDR 1997. p.564).The current rabbit study used 100 mg/4 Kg=25 mg/Kg, more than five timesthe maximum dose used in humans. Urethral absorption, even at an ×5maximum dose, remained below plasma levels considered toxic.Additionally, the level of plasma lidocaine from urethral absorptionmaintained a steady level for the entire measurement period in contrastto the rapid rise then decline of plasma lidocaine levels fromintravesical absorption.

EXAMPLE 5

The purpose of the study reported in Example 5 was to investigate howeffective were lower amounts of lidocaine in the urethral suppository.In this case, a suppository was made in which the lidocaine amount wasreduced to 10 mg. All other components in the suppository were keptconstant. Patients with a urethral component to their interstitialcystitis had a suppository emplaced in their urethra and after 30minutes were asked to rate their urethral component of their pain andurgency by filling out a PORIS questionnaire (patient overall rating ofsymptom improvement) at 30 minutes. As can be seen in FIG. 14, the vastmajority of patients (>80%) had significantly improved symptoms asdefined by ≧50% symptom improvement of pain (n=24) or urgency (n=19)from their urethra.

EXAMPLE 6

The purpose of the study reported in Example 6 was to investigate analternative buffer to sodium bicarbonate in the suppository. Tham (Tris)was used in the suppository as the buffer and the remaining componentswere kept the same (10 mg lidocaine and 5,000 units heparin). Patientswith a urethral component to their interstitial cystitis had asuppository emplaced in their urethra and after 30 minutes were asked torate their urethral component of their pain and urgency by filling out aPORIS questionnaire (patient overall rating of symptom improvement) at30 minutes. As can be seen in FIG. 15, all patients experienced a ≧50%or more symptom improvement of pain (n=4) from their urethra.Consequently, this experiment demonstrated that alternative buffersother than sodium bicarbonate can be used in the suppository.

EXAMPLE 7

The purpose of the study reported in Example 7 was to investigate theduration of relief from pain upon treatment with the urethralsuppository. Subjects that had received the urethral suppository with 10mg lidocaine with the 5000 units heparin and sodium bicarbonate werefollowed up after 24 hours and asked when their relief from pain ended.The median duration of relief was 4 hours. However, patients experiencedpain relief from ranging from 1 hour to 24 hours. The percentage ofpatients experiencing pain relief in various time groups is shown inFIG. 16. In light of the fact that lidocaine half life is quite short,the existence of patients with responses longer than 4 hours impliesthat the heparin contributes to the longevity of the pain relief of thesuppository.

ADVANTAGES OF THE INVENTION

Suppositories according to the present invention provide an effectiveand simple means for treatment of a number of serious urinary tractconditions, including interstitial cystitis. They are well tolerated andcan be utilized by most patients. They provide rapid relief and can beused together with other treatments, including oral administration ofagents such as sodium pentosanpolysulfate (Elmiron®). When suppositoriesaccording to the present invention are administered, they provide anefficient means of delivering an anesthetic agent such as lidocaine totissues of the urinary tract without risking the possibility ofexcessive systemic doses of the anesthetic agent.

The inventions illustratively described herein can suitably be practicedin the absence of any element or elements, limitation or limitations,not specifically disclosed herein. Thus, for example, the terms“comprising,” “including,” “containing,” etc. shall be read expansivelyand without limitation. Additionally, the terms and expressions employedherein have been used as terms of description and not of limitation, andthere is no intention in the use of such terms and expressions ofexcluding any equivalents of the future shown and described or anyportion thereof, and it is recognized that various modifications arepossible within the scope of the invention claimed. Thus, it should beunderstood that although the present invention has been specificallydisclosed by preferred embodiments and optional features, modificationand variation of the inventions herein disclosed can be resorted bythose skilled in the art, and that such modifications and variations areconsidered to be within the scope of the inventions disclosed herein.The inventions have been described broadly and generically herein. Eachof the narrower species and subgeneric groupings falling within thescope of the generic disclosure also form part of these inventions. Thisincludes the generic description of each invention with a proviso ornegative limitation removing any subject matter from the genus,regardless of whether or not the excised materials specifically residedtherein.

In addition, where features or aspects of an invention are described interms of the Markush group, those schooled in the art will recognizethat the invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. It is also to beunderstood that the above description is intended to be illustrative andnot restrictive. Many embodiments will be apparent to those of ordinaryskill in the art upon reviewing the above description. The scope of theinvention should therefore, be determined not with reference to theabove description, but should instead be determined with reference tothe appended claims, along with the full scope of equivalents to whichsuch claims are entitled. The disclosures of all articles andreferences, including patent publications, are incorporated herein byreference.

1. A urethral suppository comprising: (a) a carrier base material; (b) atherapeutic agent; and (c) a buffering agent; wherein the suppository isformed into a solid structure configured for insertion into the urethraof a patient.
 2. The urethral suppository of claim 1 wherein thesuppository has a substantially uniform composition.
 3. The urethralsuppository of claim 1 wherein the carrier base material has a meltingpoint such that the suppository is substantially melted at bodytemperature.
 4. The urethral suppository of claim 1 wherein the carrierbase material is a water soluble carrier base.
 5. The urethralsuppository of claim 1 wherein the carrier base material is at least onematerial selected from the group consisting of paraffin, theobroma oil,modified theobroma oil products, gelatins, glycerinated gelatins,polyethylene glycols (PEGs), glycerols, hydrogenated vegetable oils,cocoa butter, methyl butyl ketone (MBK), celluloses, polyvinyl alcohol,polyvinylpyrrolidone, polyacrylamide, polyphosphourethanes, polyoxylstearate, ethylene oxide polymers, and fatty acid bases.
 6. The urethralsuppository of claim 5 wherein the carrier base material comprisesmethyl butyl ketone.
 7. The urethral suppository of claim 5 wherein thecarrier base material comprises methyl butyl ketone and paraffin.
 8. Theurethral suppository of claim 1 wherein the therapeutic agent is ananesthetic agent.
 9. The urethral suppository of claim 8 wherein theanesthetic agent is present in a quantity sufficient to prevent orameliorate a urinary tract disorder.
 10. The urethral suppository ofclaim 9 wherein the urinary tract disorder is interstitial cystitis. 11.The urethral suppository of claim 9 wherein the urinary tract disorderis urethritis.
 12. The urethral suppository of claim 8 wherein theanesthetic agent is at least one anesthetic agent selected from thegroup consisting of lidocaine, benzocaine, bupivacaine, articaine,cocaine, etidocaine, flecainide, mepivacaine, pramoxine, prilocaine,procaine, chloroprocaine, oxyprocaine, proparacaine, ropivacaine,tetracaine, dyclonine, dibucaine, chloroxylenol, cinchocaine,dexivacaine, diamocaine, hexylcaine, levobupivacaine, propoxycaine,pyrrocaine, risocaine, rodocaine, and pharmaceutically acceptablederivatives and bioisosteres thereof, and combinations thereof.
 13. Theurethral suppository of claim 12 wherein the anesthetic agent is atleast one anesthetic agent selected from the group consisting oflidocaine, prilocaine, benzocaine, mepivacaine, etidocaine, articaine,bupivacaine, procaine, and tetracaine.
 14. The urethral suppository ofclaim 13 wherein the anesthetic agent is lidocaine.
 15. The urethralsuppository of claim 1 wherein the buffering agent is present in aquantity such that the buffering agent buffers the suppository at a pHthat ensures that a sufficient portion of an anesthetic agent that ispresent in the suppository is present in an uncharged state so that theanesthetic agent can cross cell membranes of cells surrounding theurethra.
 16. The urethral suppository of claim 15 wherein the bufferingagent maintains the pH of the suppository in a range of from about 7 toabout
 12. 17. The urethral suppository of claim 16 wherein the bufferingagent maintains the pH of the suppository in a range of from about 7 toabout
 9. 18. The urethral suppository of claim 1 wherein the bufferingagent is at least one buffer selected from the group consisting ofsodium bicarbonate buffer, calcium bicarbonate buffer,tris(hydroxymethyl)aminomethane (Tris or THAM), MOPS(3-(N-morpholino)propanesulfonic acid) buffer, HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) buffer, ACES(2-[(2-amino-2-oxoethyl)amino]ethanoesulfonic acid) buffer, ADA(N-(2-acetamido)2-iminodiacetic acid) buffer, AMPSO(3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer,BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, Bicine(N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris(bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS(3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO(3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES(2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO(3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid)buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N′-(3-propanesulfonic acid),buffer, HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid) buffer,MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolaminebuffer, imidazole buffer, glycine buffer, ethanolamine buffer, phosphatebuffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer,PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid) buffer, POPSO(piperazine-N,N′-bis(2-hydroxypropaneulfonic acid) buffer; TAPS(N-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer, TAPSO(3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid)buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid)buffer, tricine (N-tris(hydroxymethyl)methylglycine buffer),2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanolbuffer, and combinations thereof.
 19. The urethral suppository of claim18 wherein the buffering agent is selected from the group consisting ofsodium bicarbonate buffer and tris(hydroxymethyl)aminomethane buffer.20. The urethral suppository of claim 19 wherein the buffering agent issodium bicarbonate buffer.
 21. The urethral suppository of claim 19wherein the buffering agent is tris(hydroxymethyl)aminomethane buffer.22. The urethral suppository of claim 1 further comprising apolysaccharide.
 23. The urethral suppository of claim 22 wherein thepolysaccharide is present in the suppository in a sufficient quantity toprevent or ameliorate a urinary tract disorder.
 24. The urethralsuppository of claim 23 wherein the urinary tract disorder isinterstitial cystitis.
 25. The urethral suppository of claim 23 whereinthe urinary tract disorder is urethritis.
 26. The urethral suppositoryof claim 22 wherein the polysaccharide is at least one polysaccharideselected from the group consisting of hyaluronic acid, hyaluronan,chondroitin sulfate, pentosan polysulfate, dermatan sulfates, heparin,heparan sulfates, keratan sulfates, dextran sulfates, and carrageenan.27. The urethral suppository of claim 26 wherein the polysaccharide isheparin.
 28. The urethral suppository of claim 1 wherein the suppositoryis from about 10 mg to about 1000 mg in weight.
 29. The urethralsuppository of claim 1 wherein the suppository is from about 400 mg toabout 600 mg in weight.
 30. The urethral suppository of claim 1 whereinthe therapeutic agent is an anesthetic agent, and wherein thesuppository comprises from about 1 mg to about 100 mg of anestheticagent.
 31. The urethral suppository of claim 30 wherein the suppositorycomprises from about 30 mg to about 60 mg of anesthetic agent.
 32. Theurethral suppository of claim 1 wherein the suppository comprises fromabout 0.5 mg to about 100 mg of buffering agent.
 33. The urethralsuppository of claim 32 wherein the suppository comprises from about 1mg to about 20 mg of buffering agent.
 34. The urethral suppository ofclaim 33 wherein the suppository comprises from about 0.5 mg to about100 mg of buffering agent.
 35. The urethral suppository of claim 1wherein the suppository is in a configuration selected from the groupconsisting of a cylinder, a cone, and an ellipsoid.
 36. The urethralsuppository of claim 1 wherein the suppository is an elongated structurewith a transverse dimension of from about 1 mm to about 10 mm.
 37. Theurethral suppository of claim 1 wherein the suppository is an elongatedstructure with a transverse dimension of from about 3 mm to about 6 mm.38. The urethral suppository of claim 1 wherein the suppository is anelongated structure with a length of from about 5 mm to about 50 mm. 39.The urethral suppository of claim 38 wherein the suppository is anelongated structure with a length of from about 15 mm to about 35 mm.40. The urethral suppository of claim 1 wherein the suppositorycomprises a quantity of buffering agent that comprises from about 1percent to about 30 percent by weight of the overall weight of thesuppository.
 41. The urethral suppository of claim 1 further comprisinga quantity of a suspending agent sufficient to prevent activeingredients within the suppository from aggregating.
 42. The urethralsuppository of claim 41 wherein the suspending agent is silica.
 43. Theurethral suppository of claim 1 further comprising a therapeuticallyeffective quantity of an antibacterial agent or an antifungal agent totreat bacterial or fungal cystitis.
 44. A method for manufacturing aurethral suppository comprising the steps of: (a) combining atherapeutic agent and a buffering agent in a liquid carrier basematerial until the therapeutic agent and the buffering agent havedissolved or been suspended in the liquid carrier base material; and (b)forming the liquid carrier base material, therapeutic agent, andbuffering agent mixture into a suppository that is configured to bedeployed within the urethra of a patient.
 45. The method of claim 44wherein the method further comprises combining a polysaccharide with theliquid carrier base material.
 46. The method of claim 45 wherein thepolysaccharide comprises at least one polysaccharide selected from thegroup consisting of hyaluronic acid, hyaluronan, chondroitin sulfate,pentosan polysulfate, dermatan sulfates, heparin, heparan sulfates,keratan sulfates, dextran sulfates, and carrageenan.
 47. The method ofclaim 44 wherein the step of forming the mixture into a suppositoryresults in a finished suppository having a weight of from about 10 mg toabout 1000 mg.
 48. The method of claim 44 wherein the therapeutic agentis an anesthetic agent.
 49. The method of claim 48 wherein theanesthetic agent is lidocaine.
 50. The method of claim 44 wherein thequantity of buffering agent combined with the therapeutic agent in theliquid base material is sufficient to produce a pH of from about 7 toabout 12 in the finished suppository.
 51. A method of treating at leasta portion of the urinary tract of a patient comprising the steps of: (a)providing the urethral suppository of claim 1; (b) deploying theurethral suppository within the patient's urethra; and (c) allowing thesuppository to at least partially disintegrate and release thetherapeutic agent and the buffering agent to treat at least a portion ofthe urinary tract of the patient.
 52. The method of claim 51 whereindisintegration of the suppository comprises melting of the carrier basematerial of the suppository.
 53. The method of claim 51 whereindisintegration of the suppository comprises dissolving the carrier basematerial of the suppository.
 54. The method of claim 51 wherein thetherapeutic agent is an anesthetic agent.
 55. The method of claim 54wherein the anesthetic agent is lidocaine.
 56. The method of claim 54wherein treating at least a portion of the urinary tract of the patientcomprises treatment of interstitial cystitis.
 58. The method of claim 54wherein treating at least a portion of the urinary tract of the patientcomprises treatment of urethritis.
 59. The method of claim 54 whereinthe urethral suppository is deployed within the urethra of the patientin order to desensitize the urethra prior to insertion ofinstrumentation into the urethra.
 60. The method of claim 54 whereintreating at least a portion of the urinary tract of the patientcomprises treatment of pain associated with the urethra or bladder. 61.The method of claim 51 wherein the urethral suppository furthercomprises a polysaccharide and wherein the polysaccharide replaces orrepairs the glycosaminoglycan barrier lining the urinary tract of thepatient after insertion of the suppository into the urethra of thepatient.
 62. The method of claim 51 wherein the step of deploying theurethral suppository within the patient's urethra further comprises useof a water-based lubricant.
 63. A urethral suppository comprising aplurality of distinct layers, each layer comprising a carrier basematerial, a therapeutic agent, and a buffering agent, wherein at leastone of the identity of the carrier base material in a layer, theidentity of the therapeutic agent in a layer, the identity of thebuffering agent in a layer, the quantity of the carrier base material ina layer, the quantity of the therapeutic agent in a layer, the quantityof the buffering agent in a layer, and the shape of a layer variesbetween at least two of the layers of the suppository.
 64. The urethralsuppository of claim 63 wherein the urethral suppository comprises twolayers.
 65. The urethral suppository of claim 63 wherein the urethralsuppository comprises three layers.
 66. The urethral suppository ofclaim 63 wherein the urethral suppository comprises four layers.
 67. Theurethral suppository of claim 63 wherein the therapeutic agent in atleast one layer of the urethral suppository is an anesthetic agent. 68.The urethral suppository of claim 63 wherein the therapeutic agent inall layers of the urethral suppository is an anesthetic agent.
 69. Theurethral suppository of claim 63 wherein the therapeutic agent in atleast two layers of the urethral suppository is an anesthetic agent, andwherein the anesthetic agents in two layers of the urethral suppositoryare different anesthetic agents.
 70. The urethral suppository of claim69 wherein the anesthetic agent in one layer of the urethral suppositoryis a first anesthetic agent with a rapid onset and the anesthetic agentin another layer of the urethral suppository is a second anestheticagent with a slower onset than the onset of the anesthetic agent with arapid onset, but with a longer half-life than the half-life of theanesthetic agent with a rapid onset, the layer including the firstanesthetic agent being located closer to the surface of the urethralsuppository than the layer including the second anesthetic agent. 71.The urethral suppository of claim 70 wherein the first anesthetic agentis lidocaine and the second anesthetic agent is tetracaine.
 72. Theurethral suppository of claim 63 wherein the therapeutic agent in onelayer of the urethral suppository is an anesthetic agent, and whereinthe therapeutic agent in another layer of the urethral suppository is atherapeutic agent other than an anesthetic agent, the layer includingthe anesthetic agent being located closer to the surface of the urethralsuppository than the layer including the therapeutic agent other than ananesthetic agent.
 73. The urethral suppository of claim 72 wherein theanesthetic agent is lidocaine.
 74. The urethral suppository of claim 72wherein the therapeutic agent other than an anesthetic agent is selectedfrom the group consisting of an anti-infection agent, ananti-incontinence agent, an anti-inflammatory agent, and an anti-canceragent.
 75. The urethral suppository of claim 63 wherein the urethralsuppository includes therein at least two layers differing in thecomposition or quantity of the carrier base material in the layers. 76.The urethral suppository of claim 75 wherein the two layers differ inthe concentration of an agent that regulates melting time.
 77. Theurethral suppository of claim 76 wherein the agent that regulatesmelting time is paraffin.
 78. The urethral suppository of claim 63wherein the shape of a layer varies between at least two of the layersof the suppository.
 79. The urethral suppository of claim 78 wherein atleast one of the layers of the suppository is shaped to focus the effectof the suppository in a specific section of the suppository.
 80. Theurethral suppository of claim 63 wherein one or more of the layersfurther includes a polysaccharide.
 81. The urethral suppository of claim70 wherein more than one layer includes a polysaccharide, and at leastone of the identity of the polysaccharide in a layer and the quantity ofthe polysaccharide in the layer varies between at least two of thelayers of the suppository.
 82. The urethral suppository of claim 63wherein at least one of the layers includes a suspending agent.
 83. Theurethral suppository of claim 63 wherein at least one of the layersincludes a therapeutically effective quantity of an antibacterial agentor an antifungal agent.
 84. A method for manufacturing a multilayeredsuppository comprising the steps of: (a) combining a therapeutic agentand a buffering agent in a liquid carrier base material until thetherapeutic agent and the buffering agent have dissolved or beensuspended in the liquid carrier base material; and (b) forming theliquid carrier base material, therapeutic agent, and buffering agentmixture into one or more layers of a multi-layered suppository that isconfigured to be deployed within the urethra of a patient.
 85. A methodof treating at least a portion of the urinary tract of a patientcomprising the steps of: (a) providing the multilayered urethralsuppository of claim 63; (b) deploying the multilayered urethralsuppository within the patient's urethra; and (c) allowing themultilayered suppository to disintegrate and release the therapeuticagent and the buffering agent from at least one of the layers of themultilayered suppository to treat at least a portion of the urinarytract of the patient.
 86. The method of claim 85 wherein disintegrationof the suppository comprises melting of the carrier base material of atleast one layer of the suppository.
 87. The method of claim 85 whereindisintegration of the suppository comprises dissolving the carrier basematerial of at least one layer of the suppository.
 88. The method ofclaim 85 wherein treating at least a portion of the urinary tract of thepatient comprises treatment of interstitial cystitis.
 89. The method ofclaim 85 wherein treating at least a portion of the urinary tract of thepatient comprises treatment of urethritis.
 90. The method of claim 85wherein the urethral suppository is deployed within the urethra of thepatient in order to desensitize the urethra prior to insertion ofinstrumentation into the urethra.
 91. The method of claim 85 whereintreating at least a portion of the urinary tract of the patientcomprises treatment of pain associated with the urethra or bladder. 92.The method of claim 85 wherein the step of deploying the urethralsuppository within the patient's urethra further comprises use of awater-based lubricant.
 93. A depot for luminal drug delivery comprising:(a) a carrier base material; (b) a therapeutic agent; and (c) abuffering agent; wherein the depot is formed into a solid structureconfigured for insertion into a body lumen of a patient.
 94. The depotof claim 93 wherein the depot has a substantially uniform composition.95. The depot of claim 93 further comprising a polysaccharide.
 96. Thedepot of claim 93 . wherein the carrier base material has a meltingpoint such that the depot is substantially melted at body temperature.97. The depot of claim 93 wherein the therapeutic agent is an anestheticagent.
 98. The depot of claim 97 wherein the anesthetic agent islidocaine.
 99. The depot of claim 93 wherein the carrier base materialcomprises a water soluble carrier base.
 100. The depot of claim 93wherein the carrier base material comprises methyl butyl ketone.